WO2014085471A1

WO2014085471A1 - Acid-activated compositions for the treatment of cancers, methods of their use and methods of their preparation

Info

Publication number: WO2014085471A1
Application number: PCT/US2013/072034
Authority: WO
Inventors: Babak N. ALIZADEH; Kamran Tahamtanzadeh
Original assignee: Prognosdx Health, Inc.
Priority date: 2012-11-28
Filing date: 2013-11-26
Publication date: 2014-06-05

Abstract

Provided herein are compounds, compositions and methods for the treatment of cancer. In certain embodiments, the compounds comprise an acid-protecting group linked to an anti-cancer agent by an optional linker.

Description

ACID-ACTIVATED COMPOSITIONS FOR THE TREATMENT OF CANCERS, METHODS OF THEIR USE AND METHODS OF THEIR PREPARATION

FIELD

[0001 ] Provided herein are compounds, methods and pharmaceutical compositions for use in treatment of cancer. In certain embodiments, conjugate compounds are provided which display remarkable acid activation in tumor microenvironments useful for the treatment of, for example, certain cancers in a human.

BACKGROUND

[0002] Cancer is a broad group of diseases that affect millions worldwide. In 2008, there were an estimated 12.7 million cancer cases around the world, and that number was expected to increase to 21 million by the year 2030 (World Cancer Research Fund International, http^/wvv^vAvcrf.org^cancer_^statistics/world_^cance^statistics. accessed November 2012). Cancer caused approximately 13% of all deaths worldwide in the year 2004 (World Health Organization, The Global Burden of Disease: 2004 Update).

[0003] As of 2012, approximately 148 drugs are approved in the United States for cancer therapy. Of these, only about 15 new cancer drugs were approved in the year 2012, and a similar number of cancer drug approvals are expected in each of the coming years. There is clearly a need for new therapies useful for the treatment of cancer and new methods for developing new therapies useful for the treatment of cancer.

[0004] Histones provide a useful target for cancer therapeutics. Histone modification, including histone acetylation and histone methylation, govern chromosomal condensation andean have profound effects on DNA replication and repair and on gene transcription, initiation and elongation. These epigenetic effects have been identified as causes of many disease states, including many cancers. Recent efforts presented histone modifications as targets for developing new cancer therapeutics. However, histone modifications can have effects on intracellular and extracellular chemistry that can limit the utility of conventional drugs and drug candidates that target histone modifications.

[0005] New approaches are needed for the development of cancer drug candidates that target epigenetic histone modifications.

SUMMARY

[0006] Provided herein are compounds, compositions and methods useful for the development of cancer therapeutics that tolerate and, in some embodiments, are activated in the chemical micro environment of tumor cells. In particular embodiments, the compounds, compositions and methods can be particularly useful in the intracellular and/or extracellular low pH microenvironment of certain tumor cells. While not intending to be bound by any particular theory of operation, it is believed that the histone modification in certain tumor cells releases protons and/or acetate ions that can lower intracellular pH. These protons and acetate ions can be excreted into the extracellular matrix, thereby lowering the pH of the extracellular microenvironment of the tumor cell. Certain compounds, compositions and methods provided herein target histone modifications in a low pH microenvironment. In certain embodiments, the compounds and compositions maintain activity of an anti-cancer agent in the low pH microenvironment. In certain embodiments, the compounds and compositions activate an anticancer agent in the low pH microenvironment.

[0007] In one aspect, provided herein are compounds useful for the treatment of cancer in a low pH microenvironment. In certain embodiments, the compounds comprise an anti-cancer agent. The anti-cancer agent can be any such agent known to those of skill in the art, and useful anti-cancer agents are described herein. In particular embodiments, the anti-cancer agent is an epigenetic anti-cancer agent. In certain embodiments, the compounds further comprise a protecting group. The protecting group is capable of protecting the stability or activity of the anti-cancer agent in the low pH tumor microenvironment. The protecting group can be, for example, a weak base, a buffering agent, a proton sponge or a prodrug moiety. Those of skill will recognize that the protecting group can protect the anti-cancer agent from attack by protons and ions in a low pH microenvironment. In certain embodiments, the protecting group is linked to the anti-cancer agent through a linker. The linker can be a covalent bond or a linker as recognized by those of skill. Exemplary linkers are described herein. In certain embodiments, the linker is capable of degrading in a low pH

microenvironment to release the active anti-cancer agent. In certain embodiments, the prodrug moiety is capable of degradingor separating in a low pH microenvironment to release the active anti-cancer agent.

[0008] In another aspect, provided herein are pharmaceutical compositions useful for the treatment of cancer in a low pH microenvironment. In certain embodiments, the

pharmaceutical compositions comprise a compound provided herein and one or more pharmaceutically acceptable carriers, excipients or diluents. In certain embodiments, the pharmaceutical compositions comprise one or more inorganic salts useful for stabilizing an anti-cancer agent in a low pH microenvironment.

[0009] In another aspect, provided herein are methods of treating cancer. In certain embodiments, the methods of treating cancer comprise the step of administering to a subject thereof a compound or pharmaceutical composition provided herein. In certain embodiments, the methods comprise the step of contacting a cancer cell with a compound or pharmaceutical composition provided herein. In certain embodiments, the methods comprise the step of contacting a tumor cell with a compound according to any of the above claims. The cancer can be any cancer known to those of skill in the art. Exemplary cancers are described herein.

[0010] In another aspect, provided herein are methods of screening for an anti-cancer agents. The methods comprise the step of assaying a candidate agent for anti-cancer activity at a pH between 6 and 7, wherein a candidate agent that displays anti-cancer activity at said pH is selected as an anti-cancer agent. Such methods are useful for identifying candidate anti-cancer agents that are particularly effective in a low pH microenvironment.

[0011] In another aspect, provided herein are methods of culturing cells comprising the step of selecting for cells with modulated levels of histone modification, modulated levels of histone acetylation, modulated levels of histone methylation, modulated levels of proton excretion, modulated levels of acetate excretion, modulated extracellular pH, or a combination thereof. These methods can be useful for identifying or developing cells that can be used to assay or screen candidate anti-cancer agents for efficacy and/or stability in a low pH microenvironment.

[0012] The compounds, compositions and methods provided herein are useful for the treatment or prevention of cancer in a subject in need thereof. In certain embodiments, the compounds, compositions and methods are useful for inducing or accelerating cell death of a cancer cell. In certain embodiments, the compounds, compoistions and methods are useful for inducing or accelerating reversion of the oncogenic phenotype of a cancer cell. For instance, in certain embodiments, the compounds, compositions and methods provided herein are capable of changing the phenotype of a cancer cell from aggressive to indolent. Indolent tumor pheontypes will be recognized by those of skill as comparable to the phenotypes of certain indolent prostate tumor cells.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0013] Provided herein are compounds, compositions and methods useful for treating cancer in a subject.

Definitions

[0014] When referring to the compounds, compositions and methods provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0015] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic,

cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1 ,2-ethane-disulfonic, 2- hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4- toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, teri-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2) salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, Ν,Ν'- dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0016] Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4- hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1 ,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4- toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-buty\ acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate,

cyclohexylsulfamate, quinate, muconate and the like.

[0017] The term "substantially free of or "substantially in the absence of with respect to a composition refers to a composition that includes at least 85 or 90% by weight, in certain embodiments 95%, 98 %, 99% or 100% by weight, of the designated enantiomer of that compound. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of enantiomers.

[0018] Similarly, the term "isolated" with respect to a composition refers to a composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of the compound, the remainder comprising other chemical species or enantiomers.

[0019] "Solvate" refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0020] As used herein, the terms "subject" and "patient" are used interchangeably herein. The terms "subject" and "subjects" refer to an animal, such as a mammal including a non- primate (e.g. , a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and for example, a human. In certain embodiments, the subject is refractory or non-responsive to current treatments for the disease. In another embodiment, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g. , a dog or a cat). In certain embodiments, the subject is a human.

[0021] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes a compound provided herein. In certain embodiments, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.

[0022] "Therapeutically effective amount" refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A "therapeutically effective amount" can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0023] "Treating" or "treatment" of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, "treating" or "treatment" includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, "treating" or "treatment" includes modulating the disease or disorder, either physically {e.g., stabilization of a discernible symptom) or physiologically {e.g., stabilization of a physical parameter) or both. In yet another embodiment, "treating" or "treatment" includes delaying the onset of the disease or disorder.

[0024] As used herein, the terms "prophylactic agent" and "prophylactic agents" as used refer to any agent(s) which can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" includes a compound provided herein. In certain other embodiments, the term "prophylactic agent" does not refer a compound provided herein. For example, a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression and/or severity of a disorder.

[0025] As used herein, the phrase "prophylactically effective amount" refers to the amount of a therapy {e.g. , prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence, metastases or onset of one or more symptoms associated with a disorder (, or to enhance or improve the prophylactic effect(s) of another therapy {e.g., another prophylactic agent).

Compounds

[0026] Provided herein are compounds useful for the treatment of cancer in a low pH microenvironment. In certain embodiments, the compounds comprise an anti-cancer agent, a protecting group and an optional linker linking the anti-cancer agent and the protecting group. In certain embodiments, the protecting group protects the efficacy and/or stability of the anticancer agent in a low pH microenvironment.

[0027] In certain embodiments, provided herein are compounds according to Formula I:

PD - L - A

(I)

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof. In Formula I: PD is a protecting group;

L is linker; and

A is an anti-cancer agent.

[0028] The protecting group can be any protecting group recognized by those of skill. In certain embodiments, the protecting group is capable of protecting the anti-cancer agent in a low pH microenvironment. In certain embodiments, the protecting group is capable of protecting the anti-cancer agent below pH 7. In certain embodiments, the protecting group is capable of protecting the anti-cancer agent at a pH between 6 and 7. In certain embodiments, PD and/or L are capable of degrading at low pH to release the active anti-cancer agent A. In certain emboiments, PD is not linked to A and can be administered prior to or simultaneously with A or another therapy to improve therapeutic effect by first neutralizing the tumor intracellular or extracellular pH. In certain embodiments, PD is capable of protecting A by neutralizing a low pH microenvironment, for instance, as seen in and around tumor cells. In certain embodiments, PD is capable of both degrading at low pH and neutralizing a low pH microenvironment. In certain embodiments, PD is capable of of neutralizing a low pH microenvironment when linked to A. In certain embodiments, PD is capable of of neutralizing a low pH microenvironment after release from A, for instance on degradation of PD and/or L at low pH. In certain embodiments, PD is capable of neutralizing a low pH microenvironment before and after release.

[0029] In certain embodiments, the protecting group is selected from the group consisting of proton sponges, proton caging agents and acetate caging agents. These groups can be any such groups recognized by those of skill in the art. In certain embodiments, the protecting group is selected from the group consisting of l,8-bis(dimethylamino)-naphthalene (DMAN a non-nucleophilic sponge); N,N,N',N'-tetramethylnaphthalene-l,8-diamine; 8-dialkylamino- naphth-l-yl (DAN); l,8-bis(hexamethyltriaminophosphazenyl)-naphthalene (HMPN);

polyethylenimines; permethyl-PEI; perethyl-PEI; bis-l,l,8,8-(tetramethylguanidino) naphtalene (TMGN); 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); and 1,5,7- Triazabicyclo(4.4.0)dec-5-ene (TBD).

[0030] In certain embodiments, the protecting group is selected from the group consisting of 2,6-di-tert-butyl-4-methyl pyridine; 1 ,4-diazabicyclo [2.2.2] octane; 1,5-diazabicyclo [4.3.0] non-5-ene; 1,8-diazabicyclo [5.4.0] undec-7-ene; diisopropylamide anion; N,N- diisopropylethylamine; l,8-bis(dimethyl amino)naphthalene; Ν,Ν-dimethyl aniline; diphenyl amide anion; Ν,Ν,Ν,Ν-tetramethylethylene diamine; triethylamine; trimethylamine; 2,4,6- trimethylpyridine; bis(trimethylsilyl)amide anion; and triphenylmethyl anion. [0031] In certain embodiments, the protecting group is a proton sponge. In certain embodiments, the protecting group is selected from the group consisting of tertiary alkoxide ions, tertiary amines, charged or neutral lewis bases, bicarbonate ions, tertiary butyl alkoxides, tertiary butyl carbanions, tertiary carbanions, carbonate ions, isopropyl anions, nitranions, strychnine, free hydroxyl groups and anionic groups.

[0032] In certain embodiments, the protecting group is selected from the group consisting of oligonucleotides and negatively charged peptides. The oligonucleotide can be any oligonucleotide deemed suitable by those of skill. It can be of any length and any sequence deemed suitable by those of skill. In certain embodiments, the oligonucleotide is non-coding RNA or DNA. The charged peptide is preferably negatively charged. In particular embodiments, the charged peptide comprises one or more glutamate residues and/or one or more aspartate residues. In certain embodiments, the protecting group is one or more negatively charged amino acids. The amino acid can be glutamate, aspartate, a polymer of glutamate, a polymer of aspartate or a polymer of glutamate and aspartate. In certain embodiments, the protecting group is a GALA peptide, for instance a peptide having a repeating sequence of glutamate-alanine-leucine-alanine for up to 30 amino acids or more.

[0033] In certain embodiments, the protecting group is bicarbonate.

[0034] In the compounds according to formula I, L is a linker. The linker can be any linker deemed suitable by those of skill in the art. The linker can be a covalent bond, or it can comprise one or more atoms that form covalent bonds linking the protecting group to the anticancer agent. In particular embodiments, L is a divalent moiety that bonds to the protecting group and to the anti-cancer agent. Useful linkers include a bond, alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, arylene, substituted arylene, heteroarlyene and substituted heteroarylene. In particular embodiments, L is a bond, C_1-10 alkylene or C_1-10 heteroalkylene.

[0035] In advantageous embodiment, L is an acid-sensitive linker. Those of skill will recognize that an acid-sensitive linker can degrade in a low pH microenvironment, such as that of a tumor cell, to release the intact anti-cancer agent. In certain embodiments, linker L comprises an acid-sensitive group selected from the group consisting of esters, acetals, ketals, imines, hydrazones, acylhydrazones and sulfonylhydrazones. Exemplary acid-sensitive linkers are described in U.S. Patent Application Publication No. 2012/0165296 and U.S. Patent Nos. 4,997,913, 5,306,809, 5140,013, and 6,030,997, the contents of which are hereby incorporated by reference in their entireties. In certain embodiments, linker L is stable at physiological pH. In certain embodiments, linker L is cleaved at a pH between 6 and 7.

[0036] Those of skill in the art will recognize that the linker L can be bonded to any functional group of the anti-cancer agent A deemed suitable by one of skill in the art. The linker L can also be bonded, in turn, to any functional group of the protecting group PD deemed suitable by those of skill in the art. In useful embodiments, the functional groups are selected so that the linker L does not interfere excessively with the function of the anti-cancer agent A or the function of the protecting group PD.

[0037] The anti-cancer agent A can be any anti-cancer agent known to those of skill in the art. In particularly useful embodiments, the anti-cancer agent A is an epigenetic anti-cancer agent. Exemplary anti-cancer agents for use in the compounds include histone deacetylase inhibitors (HDACi's), sirtuin inhibitors (SIRTi's), histone methyl transferase inhibitors (HMTi's), histone dimethyl inhibitor (HDMi's), DNA methyltransferase inhibitors

(DNMTi's), NHE1 inhibitors, ion transporter inhibitors, DHFR pathway drugs (e.g. 5-fluoro- uracil, 5-fluorocytosine, Xeloda (Capecitabine), Tegafur and thymidylate synthase inhibitors), inhibitors of heat shock protein, HSP90 inhibitors, and monocarboxyl transport inhibitors.

[0038] The anti-cancer agent A can be activated further by other intracellular components and biomarkers including but not limited to CYP450, thymidine phosphorylase (TP), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD); ratio of TP/DPD; TS and DPD polymorphism; UPD-glucuronosyltransferase (UGT)lAl, (UGT)1A6, and

(UGT)1A7 polymorphisms.

[0039] In certain embodiments, anti-cancer agent A is selected from the group consisting of histone deacetylase inhibitors and histone demethylase inhibitors. In certain embodiments, anti-cancer agent A is selected from inhibitors of deacetylation at H4K16Ac, H3K18Ac, H4K12Ac or H3K9Ac, H4 5Ac, or combinations thereof. In certain embodiments, anticancer agent A is selected from inhibitors of demethylation at H3K4mel , H3K4me2, H3K4me3, H4K20me3, H3K27mel, H3K27me2, H3K27me3, H3K9me3, H3K9me2, H3K9mel , H4R3me2, H3K36me2, or H3 79mel , or H3K79me2, or H3K79me3 or combinations thereof. In certain embodiments, anti-cancer agent A is selected from the group consisting of chemotherapeutics, biotherapeutics, NHE1 inhibitors, DNMT inhibitors, HDM inhibitors and HSP90 inhibitors. In certain embodiments, anti-cancer agent A is selected from the group consisting of H3K18 deacetylation inhibitors and SIRT7 inhibitors. In certain embodiments, anti-cancer agent A is selected from the group consisting of H4K16

deacetylation inhibitors and SIRT2 inhibitors.

[0040] In certain embodiments, the anti-cancer agent inhibits histone deacetylase activity at H4K16Ac, H3K18Ac, H4K12Ac, H4K5Ac and/or H3K9Ac. In certain embodiments, the anti-cancer agent inhibits histone demethylase activity at H3K4mel, H3K4me2, H3 4me3, H4K20me3, H3K27me2, H3K27mel, H3K27me2, H3K27me3, H3K9me3, H3K9me2, H3K9mel, H4R3me2, H3K36me2 and/or H3K79mel, or H3K79me2, or H3 79me3. In certain embodiments, the anti-cancer agent inhibits the histone deacetylase enzymes targeting H4K16, for example the enzymes TIP60 and/or SIRT2. In certain embodiments, the anticancer agent inhibits the histone deacetylase enzymes targeting H3K18, for example the enzymes CBP/P300, PCAF and/or SIRT7. In certain embodiments, the anti-cancer agent inhibits the histone demethylase or deacetylase enzymes targeting H3, H3 9, H3K14, H3 18 and/or H3K23, for example the enzyme GCN5. In certain embodiments, the anti-cancer agent inhibits the histone demethylase or deacetylase enzymes targeting H4K12, for example the enzymes TIP60 and/or HBOl . In certain embodiments, the anti-cancer agent inhibits the histone demethylase or deacetylase enzymes targeting H3 9, for example the enzymes SUV39H1, SUV39H2, PCAF and/or G9a. In certain embodiments, the anti-cancer agent inhibits the histone deacetylase enzymes targeting H3 4, for example the enzymes MLL1, MLL2, MLL, 3, MLL4, MLL5, SETla, SETlb, SET7/9 and/or ASH1. In certain

embodiments, the anti-cancer agent inhibits the histone demethylase enzymes targeting H3K27, for example the enzyme EZH2. In certain embodiments, the anti-cancer agent inhibits the methyltransferase enzymes targeting H3K36, for example the enzymes NSD family Set2- related NSD2 (MMSET/WHSC1) and/or MES-4. In certain embodiments, the anti-cancer agent inhibits the methyltransferase enzymes targeting H3K79, for example the enzyme DOT 1L (DOT 1 -Like).

[0041] Useful DOT1L inhibitors include EPZ-5676.

[0042] Useful HDAC inhibitors include SAHA (Zolinza or N-hydroxy-N'- phenyloctanediamide), MS-275, LAQ-824, FK-228, PXD-101, valproic acid, sodium phenylbutyrate, CI-994 (Tacedinaline; PD-123654; GOE-5549; Acetyldinaline or 4- (acetylamino)-N-(2-aminophenyl)benzamide), MS-275 (SNDX-275; MS-27-275; Entinostat or pyridin-3-ylmethyl 4-(2-aminophenylcarbamoyl)benzylcarbamate), BML-210 (N-(2- aminophenyl)-N'-phenyloctanediamide), M344, NBM-HD- 1 (Belinostat or PXD101) a hydroxamate-type inhibitor, MGCD0103 (Mocetinostat), Panobinostat or LBH-589, a hydroxamic acid based HDACi (SNDX-275 or MS-275 or (E)-N-hydroxy-3-[4-[[2-(2-methyl- lH-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide), Dacinostat (LAQ824 or ((E)-N- hydroxy-3-[4-[[2-hydroxyethyl-[2-(lH-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enarnide, CHR-3996, CHR-2845, CHR-5154, M -0683, phenylbutiric acid, zebularine, Depsipeptide, psammaplin, FCDR, Mocetinostat (MGCD0103), MCI 568, M344, PI3K HDAC

Inhibitor?PCI-340 1, CI994 (Tacedinaline), Tubastatin A HC1, AR-42 (HDAC-42, OSU- HDAC42), ITF2357 (Givinostat), SB939 (Pracinostat), Droxinostat (CMH, 5809354), CUDC- 101, JNJ-26481585 (Quisinostat) , LAQ824 (NVP-LAQ824) , PCI-24781, Mocetinostat, (MGCD0103), SB939, AR-42and SRT501.

[0043 ] Other useful HDAC inhibitors target HD AC 11 and/or HDAC6. Useful HDAC 11 inhibitors include MGCD0103 (mocetinostat). Useful HDAC6 inhibitors include droxinostat (CMH, 5809354), tubastatin A and PCI-24781 (CRA-024781).

[0044] Other useful anti-cancer agents include those targeting histone-lysine N- methyltransferase EZH2 or bromodomains including but not limited to azacytidine (Vidaza), Decitabine (Dacogen), Romidepsin (Istodax) and Sulforaphane. They also include drugs targeting HGMNl, MOF, Peroxisome proliferator-activated receptors (PPARs), GCN5, PCAF, ELK4, NME1, COPS2 and SIRT7.

[0045 ] Useful monbocarboxyl transport inhibitors (MCTi) include AR-C 155858, AR- C 117977, epigallocatechin gallate (EGCG, also known as epigallocatechin-3-gallate) and cyano-4-hydroxycinnamic acid (CNCn).

[0046] Useful NHE-1 inhibitors include cariporide and KR-32 68.

[0047] In certain embodiments, the anti-cancer agent is a bromodomain inhibitor. Useful bromodomain inhibitors are describe in U.S. Patent Application Publication No. 2012/0157428 Al, the contents of which are hereby incorporated by reference in their entirety.

[0048] In certain embodiments, the anti-cancer agent is a substituted purine or substituted 7-deazapurine compound. Useful compounds are described in U.S. Patent Application Publication No. 2012/0142625 Al, the contents of which are hereby incorporated by reference in their entirety.

[0049] In certain embodiments, the anti-cancer agent is TH-302 (Threshold Pharma).

[0050] In certain embodiments, the anti-cancer agent is an agent that inhibits Ras or a mutant Ras. Exemplary agents include salirasib and sorafenib (Onyx Pharmaceuticals).

[0051] In certain embodiments, the compound further comprises a fluorescent group. The fluorescent group can be any fluorescent group recognized by those of skill. Useful fluorescent groups can be selected from the group consisting of FITC, BODIPY,

phycobiliproteins (including phycoerythrin), energy-transfer conjugates of phycobiliproteins, peridinin chlorophyllin protein, Cascade Blue, AMCA, reactive indocarbocyanine, TRITC, allophycocyanin (APC), phycocyanin (PC), and indodicarbocyanine (Cy5). In certain embodiments, the compound further comprises a fluorescence switch.

[0052] In certain embodiments, the compound further comprises a radionuclide. The radionuclide can be any radionuclide deemed suitable by a person of skill. Useful

radionuclides can be selected from the group consisting of Copper (⁶¹Cu, ⁶⁴Cu, and ⁶⁷ Cu), Indium (^mIn), Technetium (^99mTc), Rhenium (¹⁸⁶Re, ¹⁸⁸Re), Gallium (⁶⁷Ga, ⁶⁸Ga), Strontium (⁸⁹Sr), Samarium (¹⁵³Sm), Ytterbium (¹⁶⁹Yb), Thallium (²⁰¹TI), Astatine (²¹¹At), Lutetium (¹⁷⁷Lu), Actinium (²²⁵Ac), Yttrium (⁹⁰Y), Antimony (¹¹⁹Sb), Tin (¹¹⁷Sn, ¹¹³Sn), Dysprosium (¹⁵⁹Dy), Cobalt (⁵⁶Co), Iron (⁵⁹Fe), Ruthenium (⁹⁷Ru, ¹⁰³Ru), Palladium (¹⁰³Pd), Cadmium (¹¹⁵Cd), Tellurium (¹¹⁸Te, ¹² Te), Barium (¹³¹Ba,¹⁴⁰Ba), Gadolinium (¹⁴⁹Gd, ¹⁵¹Gd), Terbium (¹⁶⁰Tb), Gold (¹⁹⁸Au, ¹⁹⁹Au), Lanthanum (¹⁴⁰La), and Radium ( ²³Ra, ²²⁴Ra).

[0053] In certain embodiments, the compound maintains cellular homeostasis through modulation of proton and/or acetate efflux within the nucleus of cells, normal or cancerous, or within the cellular micro environment of cancer cells. In certain embodiments, the compound inhibits depurination of caused by acidic intracellular pH. In certain embodiments, the compound sustains the activity of an active pharmaceutical ingredient. In certain

embodiments, the compound neutralizes intracellular pH. In certain embodiments, the compound neutralizes extracellular pH. In certain embodiments, the compound improves anticancer agent efficacy. In certain embodiments, the compound improved anti-cancer agent stability. In certain embodiments, the compounds have pharmacodynamics and

pharmacokinetic properties that render them not to interfere with normal cellular function were reduced pH is desirable such as the stomach or pancreas or cellular endosomal compartments.

[0054] In certain embodiments, PD is a prodrug moiety that is capable of protecting the efficacy and/or stability of the anti-cancer agent. In certain embodiments, the prodrugs are activated below pH7. In certain embodiments, the prodrugs are activated in the pH 6-7 range. In certain embodiments, the prodrugs are inactivated or less active at a pH lower than 6 and exert improved therapeutic activity at a pH in the range of 6-7.

[0055] In certain embodiments, the compounds can be administered locally to a specific organ or organs. This can be done, for example, by isolating specific arteries in one or more organs, for instance, with a specialized catheter. In certain embodiments, the administration avoids areas where physiological pH is low, for instance, in the salivary glands, duodenum and stomach. In certain embodiments, the compounds target transient pH drops in the extracellular matrix that is normally basic on one luminal side & acidic on the other such as in pancreatic cancer. In certain embodiments, the compounds avoid intracellular compartments of physiologically low pH such as endosomes, lysosomes and the golgi apparatus. In certain embodiments, the compounds are activated in the nucleus. In certain embodiments, the compounds are activated in the cytostolic lumen. In certain embodiments, the compounds are inactive in cytostolic compartments and vesicles. In certain embodiments, the compounds can combine any two or more of the above features.

[0056] In certain embodiments, the compound is according to one of the following formulas:

Those of skill will recognize that the above formulas comprise the HDAC inhibitor

Trichostatin A (TSA) linked to a protecting group PD. The protecting group PD can be any protecting group described herein. In particular embodiments, the protecting group is glutamate or aspartate. In other embodiments, two protecting group PDs i.e. glutamate and aspartate can both be linked to the HDAC inhibitor on any of the available carbon moeities on the benzene ring. In certain embodiments, the compound is according to one of the following formulas:

Those of skill will recognize that the above formulas comprise the HDAC inhibitor TSA linked to glutamate or to aspartate.

[0057] In certain embodiments, the compounds comprise any chemical modifications including addition of nucleophile chemical moieties resulting in temporary inactivation of the drug and formation of a prodrug capable of release of the inactivating moiety under increased hydrogen ion concentration to capture and neutralize the hydrogen and/or stop a decrease in intracellular pH while exerting anti-cancer activity from the activated prodrug.

[0058] The compounds provided herein can be prepared, isolated or obtained by any method apparent to those of skill in the art.

[0059] Compounds can be assayed for anti-cancer activity according to any assay known to those of skill in the art.

Pharmaceutical Compositions and Methods of Administration

[0060] Also provided herein are pharmaceutical compositions comprising any of the compounds according to the above formulas. The compounds can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the compounds disclosed herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration.

[0061 ] In particular embodiments, the pharmaceutical compositions comprise one or more inorganic salts. It is believe that the inorganic salts are capable of protecting the active compound in a low pH microenvironment. In certain embodiments, the pharmaceutical compositions comprise a phosphate salt. In certain embodiments, the pharmaceutical compositions comprise a calcium phosphate salt.

[0062] The methods provided herein encompass administering pharmaceutical compositions containing at least one compound as described herein, including a compound of general Formula I, if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another anti-cancer agent.

[0063] In clinical practice the compounds provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation {e.g. in the form of aerosols). In certain embodiments, the compound provided herein is administered orally.

[0064] Use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules. In these compositions, the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.

[0065] These compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release. [0066] Use may be made, as liquid compositions for oral administration, of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin. These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavoring products.

[0067] The compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, for example ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.

[0068] The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

[0069] The compositions can also be aerosols. For use in the form of liquid aerosols, the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be directly inhaled, the active principle is finely divided and combined with a water-soluble solid diluent or vehicle, for example dextran, mannitol or lactose.

[0070] In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g. , a compound provided herein, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment and in this context, the term

"pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in

"Remington's Pharmaceutical Sciences" by E.W. Martin.

[0071 ] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0072] Lactose free compositions provided herein can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.

Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.

[0073] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

[0074] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

[0075] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0076] Further provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0077] The pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulation can include standard carriers such as

pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject. The formulation should suit the mode of administration. In a certain embodiment, the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, for example, an animal subject, such as a mammalian subject, for example, a human subject.

[0078] A pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intra-tumoral, intra-synovial and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings. In an embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.

[0079] Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g. , aqueous or non-aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g. , crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

[0080] The composition, shape, and type of dosage forms provided herein will typically vary depending on their use. For example, a dosage form used in the initial treatment of cancer may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same cancer. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed herein will vary from one another will be readily apparent to those skilled in the art. See, e.g. , Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000).

[0081 ] Generally, the ingredients of compositions are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0082] Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food. Particular dosage forms can have about 0.1 , 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound.

[0083] In certain embodiments, provided herein are medical devices comprising the compound. The medical devices are capable of releasing the compound under conditions sufficient for treatment of cancer in a subject in need thereof. In particular embodiments, the medical devices are capable of releasing the compound during surgery or after surgery.

Dosage and Unit Dosage Forms

[0084] In human therapeutics, a doctor will determine the posology which he considers most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the disease and other factors specific to the subject to be treated. In certain embodiments, doses are from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to 50 mg per day for an adult. In certain embodiments, doses are from about 5 to about 400 mg per day or 25 to 200 mg per day per adult. In certain embodiments, dose rates of from about 50 to about 500 mg per day are also contemplated.

[0085] In further aspects, provided are methods of treating or preventing a cancer in a subject by administering, to a subject in need thereof, an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The amount of the compound or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy {e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0086] In certain embodiments, exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of subject or sample weight {e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). For compositions provided herein, in certain embodiments, the dosage administered to a subject is 0.140 mg/kg to 3 mg/kg of the subject's body weight, based on weight of the active compound. In certain embodiments, the dosage administered to a subject is between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg kg of the subject's body weight.

[0087] In certain embodiments, the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day. In certain embodiments, the daily dose is administered twice daily in equally divided doses. In certain embodiments, a daily dose range should be from about 10 mg to about 200 mg per day, in other embodiments, between about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0088] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0089] In certain embodiment, the dosage of the composition provided herein, based on weight of the active compound, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject's body weight. In another embodiment, the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg. [0090] In certain embodiments, treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein followed by one or more maintenance doses. In such embodiments, the loading dose can be, for instance, about 60 to about 400 mg per day, or about 100 to about 200 mg per day for one day to five weeks. The loading dose can be followed by one or more maintenance doses. In certain embodiments, each maintenance does is, independently, about from about 10 mg to about 200 mg per day, between about 25 mg and about 150 mg per day, or between about 25 and about 80 mg per day. Maintenance doses can be administered daily and can be administered as single doses, or as divided doses.

[0091 ] In certain embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in blood or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical

characteristics of the subject such as height, weight and age. In certain embodiments, a sufficient amount of a compound or composition provided herein is administered to achieve a steady- state concentration in blood or serum of the subject of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL. In some embodiments, loading doses can be administered to achieve steady-state blood or serum concentrations of about 1200 to about 8000 ng/mL, or about 2000 to about 4000 ng/mL for one to five days. In certain embodiments, maintenance doses can be administered to achieve a steady- state concentration in blood or serum of the subject of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL.

[0092] In certain embodiments, administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0093] In certain aspects, provided herein are unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail above. In certain embodiments, the unit dosage comprises 1 to 1000 mg, 5 to 250 mg or 10 to 50 mg active ingredient. In particular embodiments, the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient. Such unit dosages can be prepared according to techniques familiar to those of skill in the art. Methods of Use

[0094] In certain embodiments, provided herein are methods for the treatment and/or prophylaxis of cancer that includes the administration of an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the methods encompass the step of contacting a cancer cell with a compound provided herein. In certain embodiments, the methods encompass the step of contacting a tumor cell with a compound provided herein. In certain embodiments, the methods encompass the step of administering to a subject in need thereof a compound provided herein. In certain

embodiments, provided herein are methods for treating cancer in a subject. In certain embodiments, the methods encompass the step of administering to the subject in need thereof an amount of a compound effective for the treatment or prevention of cancer in combination with a second agent effective for the treatment or prevention of the cancer. The compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In certain embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.

[0095] The cancer can be any cancer recognized by those of skill in the art. In certain embodiments, the cancer is selected from the group consisting of: acute lymphoblastic leukemia (ALL); acute myeloid leukemia; adrenocortical carcinoma; AIDS-related cancers; AIDS-related lymphoma; anal cancer; appendix cancer; astrocytoma, childhood cerebellar or cerebral; basal cell carcinoma; bile duct cancer, extrahepatic; bladder cancer; bone cancer, osteosarcoma/malignant fibrous histiocytoma; brainstem glioma; brain cancer; brain tumor, cerebellar astrocytoma; brain tumor, cerebral astrocytoma/malignant glioma; brain tumor, ependymoma; brain tumor, medulloblastoma; brain tumor, supratentorial primitive

neuroectodermal tumors; brain tumor, visual pathway and hypothalamic glioma; breast cancer; bronchial adenomas/carcinoids; Burkitt lymphoma; carcinoid tumor, childhood; carcinoid tumor, gastrointestinal; carcinoma of unknown primary; central nervous system lymphoma, primary; cerebellar astrocytoma, childhood; cerebral astrocytoma/malignant glioma, childhood; cervical cancer; childhood cancers; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; colon cancer; cutaneous t-cell lymphoma; cutaneous F-cell lymphoma; desmoplastic small round cell tumor; endometrial cancer; ependymoma; esophageal cancer; Ewing's sarcoma in the Ewing family of tumors; extracranial germ cell tumor, childhood; extragonadal germ cell tumor; extrahepatic bile duct cancer; eye cancer, intraocular melanoma; eye cancer, retinoblastoma; gallbladder cancer; gastric (stomach) cancer; gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (gist); germ cell tumor: extracranial, extragonadal, or ovarian; gestational trophoblastic tumor; glioma of the brain stem; glioma, childhood cerebral astrocytoma; glioma, childhood visual pathway and hypothalamic; gastric carcinoid; hairy cell leukemia; head and neck cancer; heart cancer; hepatocellular (liver) cancer; Hodgkin lymphoma; hypopharyngeal cancer; hypothalamic and visual pathway glioma, childhood; intraocular melanoma; islet cell carcinoma (endocrine pancreas); Kaposi sarcoma; kidney cancer (renal cell cancer); laryngeal cancer; leukemias; leukemia, acute lymphoblastic (acute lymphocytic leukemia); leukemia, acute myeloid (acute myelogenous leukemia); leukemia, chronic lymphocytic (chronic lymphocytic leukemia); leukemia, chronic myelogenous (chronic myeloid leukemia); leukemia, hairy cell; lip and oral cavity cancer; liposarcoma; liver cancer (primary); lung cancer, non-small cell; lung cancer, small cell; lymphomas; lymphoma, aids-related; lymphoma, Burkitt; lymphoma, cutaneous T- cell; lymphoma, Hodgkin; lymphomas, non-Hodgkin ; lymphoma, primary central nervous system; macro globulinemia, Waldenstrom; malignant fibrous histiocytoma of

bone/osteosarcoma; medulloblastoma, childhood; melanoma; melanoma, intraocular (eye); Merkel cell carcinoma; mesothelioma, adult malignant; mesothelioma, childhood; metastatic squamous neck cancer with occult primary; mouth cancer; multiple endocrine neoplasia syndrome, childhood; multiple myeloma/plasma cell neoplasm; mycosis fungoides;

myelodysplasia syndromes; myelodysplastic/myeloproliferative diseases; myelogenous leukemia, chronic; myeloid leukemia, adult acute; myeloid leukemia, childhood acute;

myeloma, multiple; myeloproliferative disorders, chronic; nasal cavity and paranasal sinus cancer; nasopharyngeal carcinoma; neuroblastoma; non-Hodgkin lymphoma; non-small cell lung cancer; oral cancer; oropharyngeal cancer; osteosarcoma/malignant fibrous histiocytoma of bone; ovarian cancer; ovarian epithelial cancer (surface epithelial-stromal tumor); ovarian germ cell tumor; ovarian low malignant potential tumor; pancreatic cancer; pancreatic cancer, islet cell; paranasal sinus and nasal cavity cancer; parathyroid cancer; penile cancer;

pharyngeal cancer; pheochromocytoma; pineal astrocytoma; pineal germinoma; pineoblastoma and supratentorial primitive neuroectodermal tumors, childhood; pituitary adenoma; plasma cell neoplasia/multiple myeloma; pleuropulmonary blastoma; primary central nervous system lymphoma; prostate cancer; rectal cancer; renal cell carcinoma (kidney cancer); renal pelvis and ureter, transitional cell cancer; retinoblastoma; rhabdomyosarcoma, childhood; salivary gland cancer; sarcoma, Ewing family of tumors; sarcoma, Kaposi; sarcoma, soft tissue;

sarcoma, uterine; Sezary syndrome; skin cancer (nonmelanoma); skin cancer (melanoma); skin carcinoma, Merkel cell; small cell lung cancer; small intestine cancer; soft tissue sarcoma; squamous cell carcinoma; squamous neck cancer with occult primary, metastatic; stomach cancer; supratentorial primitive neuroectodermal tumor, childhood; T-cell lymphoma, cutaneous; testicular cancer; throat cancer; thymoma, childhood; thymoma and thymic carcinoma; thyroid cancer; thyroid cancer, childhood; transitional cell cancer of the renal pelvis and ureter; trophoblastic tumor, gestational; unknown primary site, carcinoma of, adult; unknown primary site, cancer of, childhood; ureter and renal pelvis, transitional cell cancer; urethral cancer; uterine cancer, endometrial; uterine sarcoma; vaginal cancer; visual pathway and hypothalamic glioma, childhood; vulvar cancer; Waldenstrom macroglobulinemia; and Wilms tumor (kidney cancer), childhood.

Second Therapeutic Agents

[0096] In certain embodiments, the compounds and compositions provided herein are useful in methods of treatment of a cancer, that comprise further administration of a second agent effective for the treatment of the cancer in a subject in need thereof. The second agent can be any agent known to those of skill in the art to be effective for the treatment of the cancer, including those currently approved by the FDA.

[0097] In certain embodiments, a compound provided herein is administered in combination with one second agent. In further embodiments, a compound is administered in combination with two second agents. In still further embodiments, a compound is

administered in combination with two or more second agents.

[0098] As used herein, the term "in combination" includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the term "in combination" does not restrict the order in which therapies {e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disorder. A first therapy {e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to {e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to {e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy {e.g., a prophylactic or therapeutic agent) to a subject with a disorder.

[0099] As used herein, the term "synergistic" includes a combination of a compound provided herein and another therapy {e.g. , a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies {e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention or treatment of a disorder). In addition, a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

[00100] In particular embodiments, administration of a compound provided herein can neutralize or reduce the acidity of a tumor microenvironment. Advantageously, this milder tumor microenvironment can facilitate or enhance the stability and/or efficacy of a second agent that is an anti-cancer agent itself. Thus, provided herein are methods that comprise the step of administering a compound or composition provided herein in combination or alternation with one or more second agents that are anti-cancer agents. It is believed that such methods can enhance the activity or stability of the second anti-cacner agenst. The second anti-cancer agent can be any anti-cancer agent known to those of skill. Examples are described herein.

[00101] In certain embodiments, provided herein are methods that comprise administering a protecting agent in combination with one or more second anti-cancer agents. The protecting agent can be any PD described herein, or a derivative thereof. The second anti-cancer agent can be any anti-cancer agent known to those of skill. Examples are described herein. It is believed that the protecting agent can neutralize or reduce the acidity of a tumor

microenvironment to facilitate or enhance the efficacy and/or stability of the one or more second anti-cancer agents.

[00102] The active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an anti-cancer agent. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially. The dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[00103] In certain embodiments, a compound provided herein and a second agent are administered to a patient, for example, a mammal, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise. For example, the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In certain embodiments, the compound provided herein and the second active agent exert their effect at times which overlap. Each second active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the compound provided herein is administered before, concurrently or after administration of the second active agent.

[00104] In certain embodiments, the compound provided herein and the second agent are cyclically administered to a patient. Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agents) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.

[00105] In certain embodiments, the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.

[00106] In other embodiments, courses of treatment are administered concurrently to a patient, i.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent. For example, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.

[00107] The second agent can act additively or synergistically with the compound provided herein. In certain embodiments, the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition. In another embodiment, a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions. In still another embodiment, a compound provided herein is administered prior to or subsequent to administration of a second agent. Also contemplated are administration of a compound provided herein and a second agent by the same or different routes of administration, e.g. , oral and parenteral. In certain embodiments, when the compound provided herein is administered concurrently with a second agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.

[00108] The dosages of the second agents are to be used in the combination therapies provided herein. In certain embodiments, dosages lower than those which have been or are currently being used to prevent or treat cancer are used in the combination therapies provided herein. The recommended dosages of second agents can be obtained from the knowledge of those of skill. For those second agents that are approved for clinical use, recommended dosages are described in, for example, Hardman et al, eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9^th Ed, Mc-Graw-Hill, New York;

Physician's Desk Reference (PDR) 57^th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety.

[00109] In various embodiments, the therapies {e.g. , a compound provided herein and the second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart. In various embodiments, the therapies are administered no more than 24 hours apart or no more than 48 hours apart. In certain embodiments, two or more therapies are administered within the same patient visit. In other embodiments, the compound provided herein and the second agent are administered concurrently.

[00110] In other embodiments, the compound provided herein and the second agent are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.

[00111] In certain embodiments, administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments,

administration of the same agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[00112] Examples of useful second agents include J J-2641585, velcade, dexamethasone, JNJ 26481585, sorafenib, CKD-581, eltrombopa, cytarabine, imatinib mesylate, 5-fluorouracil, 5-fluorocytosine, Xeloda (Capecitabine), Tegafur, fludarabine, FR901228 (Romidepsin), NPI- 0052, capecitabine, cisplatin, Broccoli sprout extract (BSE) placebo, ACY-1215, lenalidomide, bortezomib, 4SC-202, pivanex, SHP-141, temsirolimus, hydroxychloroquine (HCQ), apatinib ditosylate, paclitaxel, trastuzumab, doxorubicin, cyclophosphamide, hydralazine and magnesium valproate, nicotinamide, MS-275 (BAY86-5274), givinostat (ITF2357), GM-CSF, ruxolitinib, cisplatin, etoposide, MGCD0103, belinostat, carboplatin, paclitaxel, bevacizumab, HAART, Pivanex, docetaxel, carfilzomib, bexarotene, rituximab, cyclophosphamide, etoposide, prednisone, vorinostat and qol questionnaire, peg-filgrastim or filgrastim, sorafeni, decitabine, tamoxifen, clofarabine, karenitecin, lenalidomide, dexamethasoneenalidomide, cyclophosphamide, dexamethasone, thalidomide, lenalidomide maintenance, lenalidomide plus vorinostat maintenance, methotrexate, imatinib mesylate, irinotecan, hydrochloride leucovorin calcium, alvocidib, erlotinib, lapatinib, temozolomide, dasatinib, gemcitabine hydrochloride and idarubicin.

Kits

[00113] Also provided are kits for use in methods of treatment of cancer. The kits can include a compound or composition provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating the disorder. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. A unit dose of a compound or composition provided herein, or a second agent or composition, can include a dosage such that when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the subject for at least 1 days. In some embodiments, a compound or composition can be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition.

[00114] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.

Assays and Cell Cultures

[00115] In certain embodiments, provided herein are methods of screening for an anticancer agent. In certain embodiments, the methods comprise the step of assaying a candidate agent for anti-cancer activity at a pH between 6 and 7, wherein a candidate agent that displays anti-cancer activity at said pH is selected as an anti-cancer agent. It is believed that assaying at a low pH will identify candidates that will have advantageous activity in the low pH microenvironment of a cancer cell. In certain embodiments, the assay ing is in a cell that has decreased histone modification relative to wild-type cells. In certain embodiments, the assaying is in a cell that has increased excretion of protons or acetate, or both, relative to wild- type cells. In certain embodiments, the assaying is in a cell that is in contact with an extracellular matrix at said pH. In certain embodiments, the assaying is conducted in vitro. In certain embodiments, the assaying is conducted in vivo.

[00116] The pH of the assay media can be maintained by any technique apparent to those of skill. In certain embodiments, the pH can be maintained with a pH buffer. Useful pH buffers will be apparent to those of skill. Exemplary pH buffers include bicarbonate (including sodium or calcium salts), TRIS, TRISMA, BIS-TRIS, BIS-TRIS propane, TES, HEPES and its salts, MES and its salts, MOPS and its salts, DISPO, HEPPSO and TAPSO.

[00117] In certain embodiments, provided herein are methods of culturing cells. The cells can be useful, for example, for screening and identifying candidate agents for the treatment of cancer. In certain embodiments, the methods comprise the step of selecting for cells with modulated levels of histone modification. In certain embodiments, the methods comprise the step of selecting for cells with modulated levels of histone acetylation. In certain

embodiments, the methods comprise the step of selecting for cells with modulated levels of histone methylation. In certain embodiments, the methods comprise the step of selecting for cells with modulated levels of proton excretion. In certain embodiments, the methods comprise the step of selecting for cells with modulated levels of acetate excretion. In certain embodiments, the methods comprise the step of selecting for cells with modulated extracellular pH. In certain embodiments, the methods comprise selecting for a combination of two or more of the above features.

[00118] All publications and patent, applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. While the claimed subject matter has been described in terms of various embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the subject matter limited solely by the scope of the following claims, including equivalents thereof.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I :

PD - L - A

(I)

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein

PD is a protecting group, and

L is an optional acid-sensitive linker; and

A is an anti-cancer agent.

2. The compound of claim 1 wherein PD is selected from the group consisting of weak basic groups, proton sponges, proton caging agents, acetate caging agents and prodrugs.

3. The compound of claim 1 further comprising a fluorescent group or a radionuclide, or both.

4. The compound of claim 1 wherein PD is selected from the group consisting of glutamate, poly-glutamate, aspartate, poly-aspartate and poly-(glutamate-aspartate).

5. The compound of claim 1 wherein PD is selected from the group consisting of oligonucleotides and negatively charged peptides.

6. The compound of claim 1 wherein PD is bicarbonate.

7. The compound of claim 1 wherein L is a linker comprising an acid-sensitive group selected from the group consisting of esters, acetals, ketals, imines, hydrazones, acylhydrazones and sulfonylhydrazones.

8. The compound of claim 1 wherein A is an epigenetic anti-cancer agent.

9. The compound of claim 1 wherein A is selected from the group consisting of HDAC inhibitors and MCT-1 inhibitors.

10. The compound of claim 1 wherein A is selected from the group consisting of histone deacetylase inhibitors and histone demethylase inhibitors.

11. The compound of claim 1 wherein A is selected from inhibitors of deacetylation at H4K16Ac, H3K18Ac, H4K12Ac, H4K5Ac, or H3K9ac, or combinations thereof.

12. The compound of claim 1 wherein A is selected from inhibitors of

demethylation at H3K4mel, H3K4me2, H3K4me3, H4K20me3, H3K27mel, H3K27me2, H3K27me3, H3K9mel, H3K9me3, H3K9me2, H4R3me2, H3K36me2, or H3K79mel, H3K79me2, H3K79me3, or combinations thereof.

13. The compound of claim 1 wherein A is selected from the group consisting of chemotherapeutics, biotherapeutics, NHEl inhibitors, DNMT inhibitors, HDM inhibitors and HSP90 inhibitors.

14. The compound of claim 1 wherein A is selected from the group consisting of H3K18 deacetylation inhibitors and SIRT7 inhibitors.

15. The compound of claim 1 wherein A is selected from the group consisting of H4K16 deacetylation inhibitors and SIRT2 inhibitors.

16. The compound of claim 1 wherein L is stable at physiological pH.

17. The compound of claim 1 wherein L is cleaved at a pH between 6 and 7.

18. The compound of claim 1 that inhibits depurination of DNA or RNA caused by acidic intracellular pH.

19. The compound of claim 1 that sustains the activity of an active pharmaceutical ingredient.

20. The compound of claim 1 that neutralizes intracellular pH

21. The compound of claim 1 that neutralizes extracellular pH.

22. The compound of claim 1 that improves drug efficacy.

23. A pharmaceutical composition comprising the compound of any of the preceding claims and one or more pharmaceutically acceptable carriers, excipients or diluents.

24. The pharmaceutical composition of claim 13 that comprises an inorganic salt.

25. The pharmaceutical composition of claim 13 that comprises phosphate or calcium phosphate.

26. A method of treating cancer comprising the step of contacting a cancer cell with a compound according to any of the above claims.

27. A method of treating cancer comprising the step of contacting a tumor cell with a compound according to any of the above claims.

28. A method of treating cancer comprising the step of administering to a subject in need thereof a compound according to any of the above claims.

29. The method of treatment of any of the previous claims wherein said compound or composition is administered in combination or alternation with one or more second agents.

30. The method of the previous claim wherein said one or more second agents are selected from the group consisting of anti-cancer agents.

31. A method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of one or more anti-cancer agents in combination or alternation with an acid-protecting agent.

32. The method of the preceding claim wherein said acid protecting agent is selected from the group consisting of proton sponges, bicarbonate and weak bases.

33. The method of any of the preceding claims wherein said anti-cancer agent is selected from the group consisting of HDAC inhibitors and MCT-1 inhibitors.

34. The method of any of the preceding claims wherein said anti-cancer agent is selected from the group consisting of histone deacetylase inhibitors and histone demethylase inhibitors.

35. The method of any of the preceding claims wherein said anti-cancer agent is selected from inhibitors of deacetylation at H4K16Ac, H3K18Ac, H4K12Ac, H4K5Ac, or H3K9ac, or combinations thereof.

36. The method of any of the preceding claims wherein said anti-cancer agent is selected from inhibitors of demethylation at H3K4mel, H3K4me2, H3K4me3, H4K20me3, H3K27mel, H3K27me2, H3K27me3, H3K9mel, H3K9me3, H3K9me2, H4R3me2, H3K36me2, or H3K79mel, H3K79me2, H3K79me3, or combinations thereof.

37. The method of any of the preceding claims wherein said anti-cancer agent is selected from the group consisting of chemotherapeutics, biotherapeutics, NHEl inhibitors, DNMT inhibitors, HDM inhibitors and HSP90 inhibitors.

38. The method of any of the preceding claims wherein said anti-cancer agent is selected from the group consisting of H3 18 deacetylation inhibitors and SIRT7 inhibitors.

39. The method of any of the preceding claims wherein said anti-cancer agent is selected from the group consisting of H4 16 deacetylation inhibitors and SIRT2 inhibitors.

40. A method of screening for an anti-cancer agent comprising the step of assaying a candidate agent for anti-cancer activity at a pH between 6 and 7, wherein a candidate agent that displays anti-cancer activity at said pH is selected as an anti-cancer agent.

41. The method of the preceding claim wherein said assaying is in a cell that has decreased histone modification relative to wild-type cells.

42. The method of any of the preceding claims wherein said assaying is in a cell that has increased excretion of protons or acetate, or both, relative to wild-type cells.

43. The method of any of the preceding claims wherein said assaying is in a cell that is in contact with an extracellular matrix at said pH.

44. The method of any of the preceding claims that is conducted in vitro.

45. The method of any of the preceding claims that is conducted in vivo.

46. A method of culturing cells comprising the step of selecting for cells with modulated levels of histone modification, modulated levels of histone acetylation, modulated levels of histone methylation, modulated levels of proton excretion, modulated levels of acetate excretion, modulated extracellular H, or a combination thereof.