WO2019057649A1 - Méthodes et compositions pharmaceutiques pour le traitement de la leucémie myéloïde aiguë - Google Patents

Méthodes et compositions pharmaceutiques pour le traitement de la leucémie myéloïde aiguë Download PDF

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WO2019057649A1
WO2019057649A1 PCT/EP2018/075003 EP2018075003W WO2019057649A1 WO 2019057649 A1 WO2019057649 A1 WO 2019057649A1 EP 2018075003 W EP2018075003 W EP 2018075003W WO 2019057649 A1 WO2019057649 A1 WO 2019057649A1
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flt3
eif6
itd
myeloid leukemia
acute myeloid
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PCT/EP2018/075003
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Stéphane MANENTI
Quentin HEYDT
Véronique DE MAS
Karine JOFFRE
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paul Sabatier Toulouse Iii
Centre National De La Recherche Scientifique (Cnrs)
Centre Hospitalier Universitaire De Toulouse
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Publication of WO2019057649A1 publication Critical patent/WO2019057649A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/50—Physical structure
    • C12N2310/53—Physical structure partially self-complementary or closed
    • C12N2310/531—Stem-loop; Hairpin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/31—Combination therapy

Definitions

  • the present invention relates to methods and pharmaceutical compositions for the treatment of acute myeloid leukemia.
  • AML Acute myeloid leukemia
  • AML patients initially respond to conventional induction therapy, relapses are common and carry a very poor prognosis (1).
  • the standard treatments for AML have remained almost unchanged over the past 40 years, demonstrating that despite improvements in our understanding of AML pathogenesis, a more in-depth knowledge of the biology of AML is still required in order to rationally design more efficient therapies.
  • extensive molecular characterization studies have highlighted the complex heterogeneity of AML (2).
  • FLT3-ITD Fms-Like Tyrosine kinase 3
  • RTK receptor tyrosine kinase
  • Autophagy is a highly-conserved catabolic process used by the cell to degrade and recycle damaged cellular components in response to adverse environmental stimuli. It relies on the formation of the autophagosome, a double-membraned vesicle that sequesters cytoplasmic bulk, proteins and organelles before fusing with lysosomes to degrade the engulfed material.
  • the role of autophagy in cancer is complex since it plays a tumor suppressor role during the early phases of tumor initiation through the prevention of genomic instability yet promotes tumor development in established tumors by promoting cancer cell survival (5).
  • oncogenes such as K-RASG12D, BRAFV600E and the fusion protein BCR-ABL1 were reported to support a high level of basal autophagy in different types of cancers which is required for cell survival and proliferation (6-8).
  • autophagy has also been described to be a mechanism of resistance to different types of drugs or treatments (9,10), and inhibiting autophagy in this context was shown to enhance treatment efficiency.
  • the publication of these studies has instigated several clinical trials combining the only available in vivo autophagy inhibitor, hydroxychloroquine (HCQ), with conventional treatments in different cancers (1 1).
  • the present invention relates to methods and pharmaceutical compositions for the treatment of acute myeloid leukemia.
  • the present invention is defined by the claims.
  • the inventors recently identified the ATF4 transcription factor as an important regulator of autophagy and proliferation in acute myeloid leukemia expressing the FLT3-ITD mutation. Here they demonstrate that ATF4 is tightly regulated by a molecular process involving the EIF6 translation initiation factor. They found that FLT3-ITD activates protein kinase C isoforms, which in turn phosphorylate the EIF6 factor on Ser235 residue, and finally activate ATF4 translation. Inhibiting PKC recapitulates the effects of FLT3-ITD inhibition or ATF4 down- regulation on cell proliferation and autophagy.
  • the first object of the present invention relates to a method of treating acute myeloid leukemia expressing the FLT3-ITD mutation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of EIF6 inhibitor.
  • acute myeloid leukemia or "AML”, also known as “acute myelogenous leukemia”
  • AML has its general meaning in the art and refers to a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells.
  • AML may be classified using either the World Health Organization classification (Vardiman J W, Harris N L, Brunning R D (2002).
  • FLT3 has its general meaning in the art and refers to a receptor tyrosine kinase that plays a role in regulating hematopoiesis.
  • FLT3 is also known as CD135, stem cell tyrosine kinase 1 (STK1), or fetal liver kinase 2 (FLK2).
  • STK1 stem cell tyrosine kinase 1
  • FLK2 fetal liver kinase 2
  • the receptor has an extracellular domain that includes five immunoglobulin-like domains, a transmembrane domain and an intracellular domain that includes a kinase domain.
  • a FLT3 receptor is activated by binding of the FMS-related tyrosine kinase 3 ligand to the extracellular domain, which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor.
  • Human FLT3 protein sequence has the UniProtKB accession number P36888.
  • An example of a human FLT3 polypeptide sequences is available under the reference sequences NP— 004110.2 in the NCBI polypeptide sequence database.
  • Example of a representative FLT3 polynucleotide sequence is available in the NCBI database under accession number NM— 004119.2.
  • FLT3 mutations are internal tandem duplications (ITDs) that lead to in-frame insertions within the juxtamembrane domain of the FLT3 receptor.
  • ITDs internal tandem duplications
  • FLT3-ITD mutations have been reported in 15- 35% of adult AML patients. See Nakao M, S Yokota and T Iwai. Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia. 1996; 10: 191 1-1918; H Kiyoi, M Towatari and S Yokota.
  • FLT3 length mutations in 1003 patients with acute myeloid leukemia correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood. 2002; 100:59-66.
  • a FLT3- ITD mutation is an independent predictor of poor patient prognosis and is associated with increased relapse risk after standard chemotherapy, and decreased disease free and overall survival. See FM Abu-Duhier, Goodeve AC, Wilson GA, et al. FLT3 internal tandem duplication mutations in adult acute myeloid leukemia define a high risk group. British Journal of Haematology.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • EIF6 has its general meaning in the art and refers to the eukaryotic translation initiation factor 6 (Gene ID: 3692).
  • the term EIF6 is also known as CAB; EIF3A; eIF-6; p27BBP; ITGB4BP; b(2)gcn; and p27(BBP).
  • An exemplary human amino acid sequence is represented by the NCBI reference sequence NP_001254739.1.
  • An exemplary human nucleic acid sequence (mRNA) is represented by the NCBI reference sequence NP 001254739.1 (SEQ ID NO: l).
  • EIF6 inhibitor refers to any compound capable of inhibiting the activity or expression of EIF6.
  • the EIF6 inhibitor of the present invention is capable of inducing massive apoptotic cell death.
  • the EIF6 inhibition may be determined by any assay well known in the art and typically the assay as described in the EXAMPLE section of the present specification.
  • said inhibitor is a small organic molecule or a biological molecule (e.g. nucleic acid, peptides, lipid, antibody, aptamer).
  • the EIF6 inhibitor is an inhibitor of EIF6 expression.
  • An "inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • said inhibitor of gene expression is a siR A, an antisense oligonucleotide or a ribozyme.
  • the inhibitor of expression is a siRNA.
  • Small inhibitory RNAs can also function as inhibitors of expression for use in the present invention.
  • EIF6 gene expression can be reduced by contacting a patient or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that EIF6 gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • the inhibitor of expression is an endonuclease.
  • the term "endonuclease” refers to enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as Deoxyribonuc lease I, cut DNA relatively nonspecifically (without regard to sequence), while many, typically called restriction endonucleases or restriction enzymes, cleave only at very specific nucleotide sequences.
  • endonuclease-based genome inactivating generally requires a first step of DNA single or double strand break, which can then trigger two distinct cellular mechanisms for DNA repair, which can be exploited for DNA inactivating: the error prone non homologous end-joining (NHEJ) and the high-fidelity homo logy-directed repair (HDR).
  • NHEJ error prone non homologous end-joining
  • HDR high-fidelity homo logy-directed repair
  • the endonuclease is CRISPR- Cas.
  • CRISPR-Cas has its general meaning in the art and refers to clustered regularly interspaced short palindromic repeats associated which are the segments of prokaryotic DNA containing short repetitions of base sequences.
  • the endonuclease is CRISPR-cas9, which is from Streptococcus pyogenes.
  • the CRISPR/Cas9 system has been described in US 8697359 Bl and US 2014/0068797.
  • the endonuclease is CRISPR-Cpfl which is the more recently characterized CRISPR from Provotella and Francisella 1 (Cpfl) in Zetsche et al. ("Cpfl is a Single RNA-guided Endonuclease of a Class 2 CRISPR-Cas System (2015); Cell; 163, 1-13).
  • the inhibitor of expression is an antisense oligonucleotide.
  • antisense oligonucleotide refers to an oligonucleotide sequence that is inverted relative to its normal orientation for transcription and so expresses an RNA transcript that is complementary to a target gene mRNA molecule expressed within the host cell (e.g., it can hybridize to the target gene mRNA molecule through Watson-Crick base pairing).
  • An antisense strand may be constructed in a number of different ways, provided that it is capable of interfering with the expression of a target gene.
  • the antisense strand can be constructed by inverting the coding region (or a portion thereof) of the target gene relative to its normal orientation for transcription to allow the transcription of its complement, (e.g., RNAs encoded by the antisense and sense gene may be complementary).
  • the antisense oligonucleotide strand need not have the same intron or exon pattern as the target gene, and noncoding segments of the target gene may be equally effective in achieving antisense suppression of target gene expression as coding segments.
  • oligonucleotide refers to a nucleic acid sequence, 3'-5' or 5'- 3' oriented, which may be single- or double-stranded.
  • the antisense oligonucleotide used in the context of the invention may in particular be DNA or R A.
  • the antisense oligonucleotide of the present invention targets an mRNA encoding EIF6 (e.g. SEQ ID NO: l), and is capable of reducing the amount of EIF6 in cells.
  • an oligonucleotide that "targets" an mRNA refers to an oligonucleotide that is capable of specifically binding to said mRNA. That is to say, the antisense oligonucleotide comprises a sequence that is at least partially complementary, preferably perfectly complementary, to a region of the sequence of said mRNA, said complementarity being sufficient to yield specific binding under intra-cellular conditions.
  • sequence that is "perfectly complementary to" a second sequence is meant the reverse complement counterpart of the second sequence, either under the form of a DNA molecule or under the form of a RNA molecule.
  • a sequence is "partially complementary to" a second sequence if there are one or more mismatches.
  • the antisense oligonucleotide of the present invention that target an mRNA encoding EIF6 may be designed by using the sequence of said mRNA as a basis, e.g. using bioinformatic tools.
  • the sequence of SEQ ID NO: 1 can be used as a basis for designing nucleic acids that target an mRNA encoding EIF6.
  • the antisense oligonucleotide according to the invention is capable of reducing the amount of EIF6 in cells, e.g. in cancerous cells.
  • Methods for determining whether an oligonucleotide is capable of reducing the amount of EIF6 in cells are known to the skilled in the art. This may for example be done by analyzing EIF6 protein expression by Western blot, and by comparing EIF6 protein expression in the presence and in the absence of the antisense oligonucleotide to be tested.
  • the antisense oligonucleotide of the present invention has a length of from 12 to 50 nucleotides, e.g. 12 to 35 nucleotides, from 12 to 30, from 12 to 25, from 12 to 22, from 15 to 35, from 15 to 30, from 15 to 25, from 15 to 22, from 18 to 22, or about 19, 20 or 21 nucleotides.
  • the antisense oligonucleotide according to the invention may for example comprise or consist of 12 to 50 consecutive nucleotides, e.g.
  • the antisense oligonucleotide of the present invention is further modified, preferably chemically modified, in order to increase the stability and/or therapeutic efficiency of the antisense oligonucleotide in vivo.
  • the antisense oligonucleotide used in the context of the invention may comprise modified nucleotides.
  • Chemical modifications may occur at three different sites: (i) at phosphate groups, (ii) on the sugar moiety, and/or (iii) on the entire backbone structure of the antisense oligonucleotide.
  • the antisense oligonucleotide may be employed as phosphorothioate derivatives (replacement of a non-bridging phosphoryl oxygen atom with a sulfur atom) which have increased resistance to nuclease digestion.
  • 2'-methoxyethyl (MOE) modification (such as the modified backbone commercialized by ISIS Pharmaceuticals) is also effective.
  • the antisense oligonucleotide of the present invention may comprise completely, partially or in combination, modified nucleotides which are derivatives with substitutions at the 2' position of the sugar, in particular with the following chemical modifications: O-methyl group (2'-0-Me) substitution, 2-methoxyethyl group (2'-0-MOE) substitution, fluoro group (2'- fluoro) substitution, chloro group (2'-Cl) substitution, bromo group (2'-Br) substitution, cyanide group (2'-CN) substitution, trifluoromethyl group (2'-CF3) substitution, OCF3 group (2'-OCF3) substitution, OCN group (2'-OCN) substitution, O-alkyl group (2'-0-alkyl) substitution, S-alkyl group (2'-S-alkyl) substitution, N-alkyl group (2'-N-akyl) substitution, O-alkenyl group (2'-0- alkenyl) substitution, S-alkenyl group (2'-S-alal
  • the antisense oligonucleotide of the present invention may comprise completely or partially modified nucleotides wherein the ribose moiety is used to produce locked nucleic acid (LNA), in which a covalent bridge is formed between the 2' oxygen and the 4' carbon of the ribose, fixing it in the 3'-endo configuration.
  • LNA locked nucleic acid
  • the antisense oligonucleotide used in the context of the invention comprises modified nucleotides selected from the group consisting of LNA, 2'- OMe analogs, 2 '-phosphorothioate analogs, 2'-fluoro analogs, 2'-Cl analogs, 2'-Br analogs, 2'- CN analogs, 2'-CF3 analogs, 2'-OCF3 analogs, 2'-OCN analogs, 2'-0-alkyl analogs, 2'-S- alkyl analogs, 2 '-N-alkyl analogs, 2 '-O-alkenyl analogs, 2 '-S-alkenyl analogs, 2 '-N-alkenyl analogs, 2'-SOCH3 analogs, 2'-S02CH3 analogs, 2'-ON02 analogs, 2'-N02 analogs, 2'-N3 analogs, 2'-NH2 analogs and combinations thereof.
  • modified nucleotides selected from the group
  • the modified nucleotides are selected from the group consisting of LNA, 2'-OMe analogs, 2'-phosphorothioate analogs and 2'-fluoro analogs.
  • the antisense is a Tricyclo-DNA antisense.
  • tricyclo-DNA refers to a class of constrained oligodeoxyribonucleotide analogs in which each nucleotide is modified by the introduction of a cyclopropane ring to restrict conformational flexibility of the backbone and to optimize the backbone geometry of the torsion angle ⁇ as (Ittig D, et al, Nucleic Acids Res, 2004, 32:346-353; Ittig D, et al, Moscow, Academy of Sciences of the Czech Republic. 1 :21-26 (Coll. Symp.
  • the tc-DNA differs structurally from DNA by an additional ethylene bridge between the centers C(3' ) and C(5' ) of the nucleosides, to which a cyclopropane unit is fused for further enhancement of structural rigidity. See e.g.
  • WO2010115993 for examples of tricyclo- DNA (tc-DNA) antisense oligonucleotides.
  • the advantage of the tricyclo-DNA chemistry is that the structural properties of its backbone allow a reduction in the length of an AON while retaining high affinity and highly specific hybridization with a complementary nucleotide sequence.
  • tc-DNA AON may be advantageously used in microgram dosages in the in vivo setting using intramuscular application, which are at least 10-fold less than the dosages required for conventional antisense oligonucleotide technologies.
  • tc-DNA retains full activity with reduced antisense lengths.
  • tc-DNA AON of 13 to 15 nucleotides are highly effective in the ex vivo and in vivo applications exemplified by the present disclosure.
  • the antisense oligonucleotide of the invention can be synthesized de novo using any of a number of procedures well known in the art. These chemistries can be performed by a variety of automated nucleic acid synthesizers available in the market. These nucleic acids may be referred to as synthetic nucleic acids. Alternatively, antisense oligonucleotide can be produced on a large scale in plasmids (see Sambrook, et al, 1989). The antisense oligonucleotide can be prepared from existing nucleic acid sequences using known techniques, such as those employing restriction enzymes, exonucleases or endonucleases.
  • the antisense oligonucleotide of the present invention is modified by substitution at the 3' or the 5' end by a moiety comprising at least three saturated or unsaturated, preferably saturated, linear or branched, preferably linear, hydrocarbon chains comprising from 2 to 30 carbon atoms, preferably from 5 to 20 carbon atoms, more preferably from 10 to 18 carbon atoms as described in WO2014195432.
  • the modified antisense oligonucleotide is of the general formula
  • Oligo represents the antisense oligonucleotide sequence of the present invention oriented 3 '-5' or 5 '-3',
  • X represents a divalent linker moiety selected from ether -0-, thio -S-, amino -NH-, and methylene -CH 2 - ;
  • Ri and R 2 may be identical or different and represent:
  • halogen in particular fluorine atom
  • Mi, M 2 and M 3 may be identical or different and represent:
  • - a saturated or unsaturated, preferably saturated, linear or branched, preferably linear, hydrocarbon chain comprising from 2 to 30 carbon atoms, preferably from 6 to 22 carbon atoms, more preferably from 12 to 20 carbon atoms, which may be substituted by one or more halogen atoms, notably be fluorinated or perfluorinated and/or be interrupted by one or more groups selected from ether -0-, thio -S-, amino -NH-, oxycarbonyl -O-C(O)-, thiocarbamate - 0-C(S)-NH-, carbonate -0-C(0)-0-, carbamate -0-C(0)-NH-, phosphate -0-P(0)(0)-0- and phosphonate -P-0(0)(0)- groups; and/or be substituted at the terminal carbon atom by an aliphatic or aromatic, notably benzylic or naphtylic ester or ether group;
  • an acyl radical with 2 to 30 carbon atoms, preferably with 6 to 22 carbon atoms, more preferably with 12 to 20 carbon atoms, or
  • alkyl refers to a hydrocarbon chain that may be a linear or branched chain, containing the indicated number of carbon atoms.
  • Ci-Ci 2 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it.
  • acyl refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl or heteroarylcarbonyl substituent.
  • the antisense modified oligonucleotide is of the general formula
  • [3'— 5'] represents, along with the P0 3 " residue, the antisense oligonucleotide of the present invention.
  • a + represents a cation, preferably H + , Na + , K + or NH 4 + .
  • the divalent linker moiety is preferably ether -0-.
  • Ri and R 2 are preferably hydrogen atoms.
  • the antisense modified oligonucleotide is of the formula (##!):
  • a + , Mi, M 2 and M 3 are as defined above in formula (I) and [3'— 5'] represents, along with the P0 3 " residue, the antisense oligonucleotide of the present invention.
  • Mi, M 2 and M 3 preferably represent a hydrocarbon chain, preferably a linear hydrocarbon chain, comprising from 6 to 22 carbon atoms, preferably from 12 to 20 carbon atoms, more preferably 18 carbon atoms.
  • the antisense modified oligonucleotide is of the formula (##! '):
  • a + is as defined above in formula (I) and [3'— 5'] represents, along with the PO3 " residue, the antisense oligonucleotide of the present invention.
  • the chains -C18H37 are preferably straight alkyl chains.
  • the antisense oligonucleotide of the present invention is modified by substitution at the 3 ' or the 5 ' end by a moiety comprising at least one ketal functional group, wherein the ketal carbon of said ketal functional group bears two saturated or unsaturated, preferably saturated, linear or branched, preferably linear, hydrocarbon chains comprising from 1 to 22 carbon atoms, preferably from 6 to 20 carbon atoms, in particular 10 to 19 carbon atoms, and even more preferably from 12 to 18 carbon atoms as described in WO2014195430.
  • the modified antisense oligonucleotide is of the general formula
  • Oligo represents the antisense oligonucleotide of the present invention
  • X represents a divalent linker moiety selected from ether -0-, thio -S-, amino -NH-, and methylene -CH2-;
  • Ri and R2 may be identical or different and represent:
  • Li and L2 may be identical or different and represent a saturated or unsaturated, preferably saturated, linear or branched, preferably linear, hydrocarbon chain comprising from 1 to 22 carbon atoms, preferably from 6 to 20 carbon atoms, more preferably from 12 to 18 carbon atoms,
  • B is an optionally substituted nucleobase, selected from the group consisting of purine nucleobases, pyrimidine nucleobases, and non-natural monocyclic or bicyclic heterocyclic nucleobases wherein each cycle comprises from 4 to 7 atoms.
  • the antisense modified oligonucleotide is of the general formula
  • [3'— 5'] represents, along with the PO3 " residue, the antisense oligonucleotide of the present invention.
  • a + represents a cation, preferably H + , Na + , K + or NH 4 + .
  • the divalent linker moiety is preferably ether -0-.
  • Ri and R 2 are preferably hydrogen atoms.
  • the antisense modified oligonucleotide is of the formula (##!):
  • a + , X, Li, L 2 and B are as defined above in formula (I) and [3 '— 5 '] represents, along with the PO3 " residue, the antisense oligonucleotide of the present invention.
  • Li and L 2 preferably represent a hydrocarbon chain, preferably a linear hydrocarbon chain, comprising from 6 to 22 carbon atoms, preferably from 8 to 18 carbon atoms, advantageously from 12 to 16 carbon atoms, more advantageously 15 carbon atoms.
  • B preferably represents a non-substituted nucleobase selected from the group consisting of uracil, thymine, adenine, guanine, cytosine, 6- methoxypurine, 7-methylguanine, xanthine, 5,6-dihydrouracil, 5-methylcytosine, 5- hydroxymethylcytosine and hypoxanthine.
  • B represents a non-substituted nucleobase selected from the group consisting of uracil, thymine, adenine, cytosine, 6-methoxypurine and hypoxanthine. More preferably, in the formulae (I), ( ⁇ ) and (I"), B represents uracil.
  • the antisense modified oligonucleotide is of the formula (##! '):
  • a + is as defined above in formula (I) and [3'— 5'] represents, along with the PO3 " residue, the antisense oligonucleotide of the present invention.
  • the antisense oligonucleotide of the present invention is associated with a carrier or vehicle, e.g., liposomes or micelles, although other carriers could be used, as would be appreciated by one skilled in the art.
  • a carrier or vehicle e.g., liposomes or micelles
  • Liposomes are vesicles made of a lipid bilayer having a structure similar to biological membranes. Such carriers are used to facilitate the cellular uptake or targeting of the antisense oligonucleotide, or improve the antisense oligonucleotide's pharmacokinetic or toxicologic properties.
  • the antisense oligonucleotide of the present invention may also be administered encapsulated in liposomes, pharmaceutical compositions wherein the active ingredient is contained either dispersed or variously present in corpuscles consisting of aqueous concentric layers adherent to lipidic layers.
  • the antisense oligonucleotide depending upon solubility, may be present both in the aqueous layer and in the lipidic layer, or in what is generally termed a liposomic suspension.
  • the hydrophobic layer generally but not exclusively, comprises phopholipids such as lecithin and sphingomyelin, steroids such as cholesterol, more or less ionic surfactants such as diacetylphosphate, stearylamine, or phosphatidic acid, or other materials of a hydrophobic nature.
  • the diameters of the liposomes generally range from about 15 nm to about 5 microns.
  • the use of liposomes as drug delivery vehicles offers several advantages. Liposomes increase intracellular stability, increase uptake efficiency and improve biological activity. Liposomes are hollow spherical vesicles composed of lipids arranged in a similar fashion as those lipids, which make up the cell membrane.
  • liposomes have an internal aqueous space for entrapping water soluble compounds and range in size from 0.05 to several microns in diameter.
  • liposomes can deliver nucleic acids to cells and that the nucleic acids remain biologically active.
  • cost-effective manufacture of liposome -based pharmaceuticals either in a liquid suspension or lyophilized product, has demonstrated the viability of this technology as an acceptable drug delivery system.
  • the antisense oligonucleotide of the present invention is complexed with a complexing agent to increase cellular uptake of oligonucleotides.
  • a complexing agent includes cationic lipids. Cationic lipids can be used to deliver oligonucleotides to cells.
  • cationic lipid includes lipids and synthetic lipids having both polar and non-polar domains and which are capable of being positively charged at or around physiological pH and which bind to polyanions, such as nucleic acids, and facilitate the delivery of nucleic acids into cells.
  • cationic lipids include saturated and unsaturated alkyl and alicyclic ethers and esters of amines, amides, or derivatives thereof.
  • Straight-chain and branched alkyl and alkenyl groups of cationic lipids can contain, e.g., from 1 to about 25 carbon atoms.
  • Preferred straight chain or branched alkyl or alkene groups have six or more carbon atoms.
  • Alicyclic groups include cholesterol and other steroid groups.
  • Cationic lipids can be prepared with a variety of counterions (anions) including, e.g., C1-, Br-, I-, F-, acetate, trifluoroacetate, sulfate, nitrite, and nitrate.
  • cationic lipids examples include: polyethylenimine, polyamidoamine (PAMAM) starburst dendrimers, Lipofectin (a combination of DOTMA and DOPE), Lipofectase, Lipofectamine, DOPE, Cytofectin (Gilead Sciences, Foster City, Calif), and Eufectins (JBL, San Luis Obispo, Calif).
  • Cationic liposomes may comprise the following: N-[l-(2,3-dioleoloxy)-propyl]-N,N,N-trimethylammonium chloride (DOTMA), N-[l-(2,3-dioleoloxy)-propyl]-N,N,N-trimethylammonium methylsulfate (DOTAP), 3p-[N-(N' , ⁇ ' -dimethylaminoethane)carbamoyl]cholesterol (DC-Choi), 2,3,- dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-l-propanaminium
  • DOSPA trifluoroacetate
  • DDAB dimethyldioctadecylammonium bromide
  • DOTMA cationic lipid N-(l-(2,3- dioleyloxy)propyl)-N,N,N-trimethylammonium chloride
  • Oligonucleotides can also be complexed with, e.g., poly(L-lysine) or avidin and lipids may, or may not, be included in this mixture (e.g., steryl-poly(L-lysine).
  • Cationic lipids have been used in the art to deliver oligonucleotides to cells (see, e.g., U.S. Pat. Nos. 5,855,910; 5,851,548; 5,830,430; 5,780,053; 5,767,099; Lewis et al. 1996. Proc. Natl. Acad. Sci. USA 93:3176; Hope et al. 1998. Molecular Membrane Biology 15: 1).
  • lipid compositions which can be used to facilitate uptake of the instant oligonucleotides can be used in connection with the claimed methods.
  • other lipid compositions are also known in the art and include, e.g., those taught in U.S. Pat. No. 4,235,871; U.S. Pat. Nos. 4,501,728; 4,837,028; 4,737,323.
  • the term "therapeutically effective amount” as used herein refers to an amount or dose of the inhibitor of the present invention that is sufficient to treat the patient.
  • the amount of the inhibitor in a given therapeutically effective combination may be different for different individuals and different tumor types, and will be dependent upon the one or more additional agents or treatments included in the combination.
  • the “therapeutically effective amount” is determined using procedures routinely employed by those of skill in the art such that an “improved therapeutic outcome” results. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts.
  • the useful dosage to be administered and the particular mode of administration will also vary depending upon the form of the formulation, for example, suspension, emulsion, micelle or liposome, as will be readily apparent to those skilled in the art.
  • the EIF6 inhibitor of the present invention is administered to the patient in combination with at least one FLT3 inhibitor.
  • FLT3 inhibitors that are contemplated by the invention include but are not limited to those described in Sternberg et al. 2004 and in International Patent Application Nos WO 2002032861, WO 2002092599, WO 2003035009, WO 2003024931, WO 2003037347, WO 2003057690, WO 2003099771, WO 2004005281, WO 2004016597, WO 2004018419, WO 2004039782, WO 2004043389, WO 2004046120, WO 2004058749, WO 2004058749, WO 2003024969, WO 2006/138155, WO 2007/048088 and WO 2009/095399 which are incorporated herein by reference.
  • FLT3 inhibitors may consist in FLT3 kinase inhibitors.
  • FLT3 kinase inhibitors include Quizartinib (AC220), AG 1295 and AG 1296; Lestaurtinib (also known as CEP-701, formerly KT-5555, Kyowa Hakko, licensed to Cephalon); CEP-5214 and CEP-7055 (Cephalon); CHIR-258 (Chiron Corp.); GTP 14564 (Merk Biosciences UK).
  • Midostaurin also known as PKC 412 Novartis AG
  • MLN-608 Millennium USA
  • MLN-518 formerly CT53518, COR Therapeutics Inc., licensed to Millennium Pharmaceuticals Inc.
  • MLN-608 Millennium Pharmaceuticals Inc.
  • SU- 11248 Pfizer USA
  • SU-11657 Pfizer USA
  • THRX-165724 Therassemble Inc.
  • AMI- 10706 Theravance Inc.
  • VX-528 and VX-680 Vertex Pharmaceuticals USA, licensed to Novartis (Switzerland), Merck & Co USA
  • XL 999 Exelixis USA
  • the EIF6 inhibitor of the invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • pharmaceutically acceptable excipients such as a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, sorbitol, sorbitol, adiluent, encapsulating material or formulation auxiliary of any type.
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • Galenic adaptations may be done for specific delivery in the small intestine or colon.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol ; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • EIF6 inhibitors of the invention in all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising EIF6 inhibitors of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the EIF6 inhibitor of the invention can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifusoluble agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the EIF6 inhibitor of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered.
  • other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; liposomal formulations ; time release capsules ; and any other form currently used.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 Impact of EIF6 down regulation on ATF4 protein expression and on autophagy.
  • MOLM-14 (FLT3-ITD) A
  • MV4-11 FLT3-ITD
  • B MV4-11
  • FLT3wt OCI-AML3
  • C OCI-AML3 cell lines expressing doxycycline-inducible shRNA against EIF6 were generated.
  • the impact of EIF6 down regulation on the ATF4 protein level and on the autophagy process was followed by western blot analysis of LC3b and ATF4 in these 3 cell lines.
  • Figure 2 Importance of EIF6 for FLT3-ITD AML cells proliferation and survival.
  • MOLM-14 shEIF6 (A-B), MV4-11 shEIF6 (C) and OCI-AML3 shEIF6 (D) cell lines were induced with doxycycline to down-regulate EIF6, and counted each day (A, C and D respectively) to estimate the importance of EIF6 in the proliferation process of these cells.
  • MOLM14 cells the impact of EIF6 down-regulation on cell death (apoptosis) was evaluated by Annexin V labelling (C).
  • FIG. 3 PKC regulates ATF4 protein level and autophagy downstream of FLT3- ITD.
  • A Protein kinase C ⁇ phosphorylation on Ser 266 was followed by western blot in MOLM-14 cells treated with FLT3-ITD inhibitor.
  • B MOLM-14 cells were treated with the PKC inhibitors Bisindolylmaleimide (Bis) or enzastaurin (Enza) for 2 hours, and ATF4 protein level was estimated by western blot.
  • C MOLM-14 cells were treated with Bisindolylmaleimide (Bis) or enzastaurin (Enza) for 16 hours in the presence or the absence of chloroquine, and the autophagy level was estimated by western blot analysis of LC3.
  • FIG. 4 Importance of EIF6 for the survival of mice engrafted with FLT3-ITD AML cells.
  • NSG mice (n 15) engrafted with MOLM-14 cells stably expressing the eIF6 inducible shR As by IV injection, were treated with sucrose (10 ⁇ g/ml) with or without doxycycline (200 ⁇ g/ml) via their drinking water and their overall survival was analyzed.
  • the graph represents the Kaplan-Meier survival curves.
  • ATF4 translation has been extensively described downstream of the EIF2alpha integrated stress pathway (for a review see 16) we asked whether this pathway could be involved in the regulation of ATF4 in the AML model. Although we observed increased phosphorylation of EIF2alpha in response to FLT3-ITD inhibition, this was correlated with quick down-regulation of ATF4, at the opposite/contrary of the process described in the literature, indicating that ATF4 is regulated though another translation pathway downstream of FLT3-ITD (data not shown). In a recent work, ATF4 was described as a target of the initiation translation factor EIF6 for the regulation of lipid metabolisms and glycolysis in the context of insulin sensitivity (17).
  • EIF6 down regulating the expression or activity of EIF6 is of a particular interest for the treatment of acute myeloid leukemia expressing the FLT3-ITD mutation.
  • Torgersen ML Engedal N, Boe SO, Hokland P, Simonsen A. Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells. Blood 2013;122:2467-2476.

Abstract

La leucémie myéloïde aiguë (AML) provient de l'expansion clonale maligne de précurseurs myéloïdes indifférenciés, conduisant à une insuffisance d'hématopoïèse de la moelle osseuse. Les anomalies génétiques les plus communes, qui se produisent chez environ 30 % des patients AML, se situent au sein du gène de la tyrosine kinase 3 de type Fms (FLT3) qui code pour une tyrosine kinase réceptrice (RTK). Les mutations les plus fréquentes dans ce gène se produisent via une duplication en tandem interne (FLT3-ITD) dans le domaine juxtamembranaire. Les inventeurs ont récemment identifié le facteur de transcription ATF4 comme régulateur important de l'autophagie et de la prolifération dans la leucémie myéloïde aiguë exprimant la mutation FLT3-ITD. Ici, ils démontrent que l'ATF4 est étroitement régulé par un processus moléculaire impliquant le facteur d'initiation de traduction EIF6. De manière plus importante, les inventeurs démontrent que la régulation négative d'interférence ARN de EIF6 induit une mort cellulaire apoptotique massive dans des cellules FLT3-ITD, tout en n'influençant pas le comportement de cellules leucémiques exprimant FLT3 de type sauvage. En conséquence, la présente invention concerne des inhibiteurs de EIF6 utilisés dans le traitement de la leucémie myéloïde aiguë exprimant la mutation FLT3-ITD.
PCT/EP2018/075003 2017-09-19 2018-09-17 Méthodes et compositions pharmaceutiques pour le traitement de la leucémie myéloïde aiguë WO2019057649A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11236171B2 (en) 2016-12-21 2022-02-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Human monoclonal antibodies specific for FLT3 and uses thereof

Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5767099A (en) 1994-12-09 1998-06-16 Genzyme Corporation Cationic amphiphiles containing amino acid or dervatized amino acid groups for intracellular delivery of therapeutic molecules
US5780053A (en) 1994-03-29 1998-07-14 Northwestern University Cationic phospholipids for transfection
US5830430A (en) 1995-02-21 1998-11-03 Imarx Pharmaceutical Corp. Cationic lipids and the use thereof
US5851548A (en) 1995-06-07 1998-12-22 Gen-Probe Incorporated Liposomes containing cationic lipids and vitamin D
WO2002032861A2 (fr) 2000-10-17 2002-04-25 Merck & Co., Inc. Sels oralement actifs a activite tyrosine kinase
WO2002092599A1 (fr) 2001-05-14 2002-11-21 Novartis Ag Derives 4-amino-5-phenyl-7-cyclobutyl-pyrrolo (2,3-d) pyrimidine
WO2003024969A1 (fr) 2001-09-14 2003-03-27 Merck & Co., Inc. Inhibiteurs des tyrosine kinases
WO2003024931A1 (fr) 2001-09-14 2003-03-27 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
WO2003035009A2 (fr) 2001-10-26 2003-05-01 Sugen, Inc. Traitement de la leucemie myeloide aigue a l'aide de composes d'indolinone
WO2003037347A1 (fr) 2001-10-30 2003-05-08 Novartis Ag Derives de staurosporine inhibiteurs de l'activite tyrosine kinase du recepteur flt3
WO2003057690A1 (fr) 2001-12-27 2003-07-17 Theravance, Inc. Derives d'indolinone utilises comme inhibiteurs de la proteine kinase
WO2003099771A2 (fr) 2002-05-29 2003-12-04 Novartis Ag Derives de diaryle-uree utilises pour le traitement des maladies dependant des proteines kinases
WO2004005281A1 (fr) 2002-07-05 2004-01-15 Novartis Ag Inhibiteurs de tyrosine kinases
WO2004016597A2 (fr) 2002-08-14 2004-02-26 Vertex Pharmaceuticals Incorporated Inhibiteurs de la proteine kinase et leurs utilisations
WO2004018419A2 (fr) 2002-08-23 2004-03-04 Chiron Corporation Quinolinones de benzimidazole et leurs utilisations
WO2004039782A1 (fr) 2002-10-29 2004-05-13 Kirin Beer Kabushiki Kaisha Derives de quinoline et de quinazoline inhibant l'autophosphorylation de flt3 et compositions medicales les contenant
WO2004043389A2 (fr) 2002-11-13 2004-05-27 Chiron Corporation Procedes de traitement du cancer et procedes connexes
WO2004046120A2 (fr) 2002-11-15 2004-06-03 Vertex Pharmaceuticals Incorporated Diaminotriazoles convenant comme inhibiteurs de proteine kinases
WO2004058749A1 (fr) 2002-12-18 2004-07-15 Vertex Pharmaceuticals Incorporated Derives de benzisoxazole utiles en tant qu'inhibiteurs des proteine kinases
WO2006138155A1 (fr) 2005-06-10 2006-12-28 Janssen Pharmaceutica N.V. Modulation synergique de kinase flt3 kinase au moyen d'un inhibiteur flt3 et d'un inhibiteur de farnesyl transferase
WO2007048088A2 (fr) 2005-10-18 2007-04-26 Janssen Pharmaceutica N.V. Methode d'inhibition de la kinase flt3
WO2009095399A2 (fr) 2008-02-01 2009-08-06 Akinion Pharmaceuticals Ab Nouveaux composés, leur utilisation et leur préparation
WO2010115993A1 (fr) 2009-04-10 2010-10-14 Association Institut De Myologie Oligonucléotides antisens tricyclo-adn, compositions, et méthodes de traitement de maladies
US20140068797A1 (en) 2012-05-25 2014-03-06 University Of Vienna Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US8697359B1 (en) 2012-12-12 2014-04-15 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
WO2014195430A1 (fr) 2013-06-05 2014-12-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Oligonucléotides antisens modifiés pour être hydrophobes comprenant un groupe cétal
WO2014195432A1 (fr) 2013-06-05 2014-12-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Oligonucléotides anti-sens modifiées par hydrophobie comprenant une chaîne alkyle triple

Patent Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5855910A (en) 1994-03-29 1999-01-05 Northwestern University Cationic phospholipids for transfection
US5780053A (en) 1994-03-29 1998-07-14 Northwestern University Cationic phospholipids for transfection
US5767099A (en) 1994-12-09 1998-06-16 Genzyme Corporation Cationic amphiphiles containing amino acid or dervatized amino acid groups for intracellular delivery of therapeutic molecules
US5830430A (en) 1995-02-21 1998-11-03 Imarx Pharmaceutical Corp. Cationic lipids and the use thereof
US5851548A (en) 1995-06-07 1998-12-22 Gen-Probe Incorporated Liposomes containing cationic lipids and vitamin D
WO2002032861A2 (fr) 2000-10-17 2002-04-25 Merck & Co., Inc. Sels oralement actifs a activite tyrosine kinase
WO2002092599A1 (fr) 2001-05-14 2002-11-21 Novartis Ag Derives 4-amino-5-phenyl-7-cyclobutyl-pyrrolo (2,3-d) pyrimidine
WO2003024969A1 (fr) 2001-09-14 2003-03-27 Merck & Co., Inc. Inhibiteurs des tyrosine kinases
WO2003024931A1 (fr) 2001-09-14 2003-03-27 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
WO2003035009A2 (fr) 2001-10-26 2003-05-01 Sugen, Inc. Traitement de la leucemie myeloide aigue a l'aide de composes d'indolinone
WO2003037347A1 (fr) 2001-10-30 2003-05-08 Novartis Ag Derives de staurosporine inhibiteurs de l'activite tyrosine kinase du recepteur flt3
WO2003057690A1 (fr) 2001-12-27 2003-07-17 Theravance, Inc. Derives d'indolinone utilises comme inhibiteurs de la proteine kinase
WO2003099771A2 (fr) 2002-05-29 2003-12-04 Novartis Ag Derives de diaryle-uree utilises pour le traitement des maladies dependant des proteines kinases
WO2004005281A1 (fr) 2002-07-05 2004-01-15 Novartis Ag Inhibiteurs de tyrosine kinases
WO2004016597A2 (fr) 2002-08-14 2004-02-26 Vertex Pharmaceuticals Incorporated Inhibiteurs de la proteine kinase et leurs utilisations
WO2004018419A2 (fr) 2002-08-23 2004-03-04 Chiron Corporation Quinolinones de benzimidazole et leurs utilisations
WO2004039782A1 (fr) 2002-10-29 2004-05-13 Kirin Beer Kabushiki Kaisha Derives de quinoline et de quinazoline inhibant l'autophosphorylation de flt3 et compositions medicales les contenant
WO2004043389A2 (fr) 2002-11-13 2004-05-27 Chiron Corporation Procedes de traitement du cancer et procedes connexes
WO2004046120A2 (fr) 2002-11-15 2004-06-03 Vertex Pharmaceuticals Incorporated Diaminotriazoles convenant comme inhibiteurs de proteine kinases
WO2004058749A1 (fr) 2002-12-18 2004-07-15 Vertex Pharmaceuticals Incorporated Derives de benzisoxazole utiles en tant qu'inhibiteurs des proteine kinases
WO2006138155A1 (fr) 2005-06-10 2006-12-28 Janssen Pharmaceutica N.V. Modulation synergique de kinase flt3 kinase au moyen d'un inhibiteur flt3 et d'un inhibiteur de farnesyl transferase
WO2007048088A2 (fr) 2005-10-18 2007-04-26 Janssen Pharmaceutica N.V. Methode d'inhibition de la kinase flt3
WO2009095399A2 (fr) 2008-02-01 2009-08-06 Akinion Pharmaceuticals Ab Nouveaux composés, leur utilisation et leur préparation
WO2010115993A1 (fr) 2009-04-10 2010-10-14 Association Institut De Myologie Oligonucléotides antisens tricyclo-adn, compositions, et méthodes de traitement de maladies
US20140068797A1 (en) 2012-05-25 2014-03-06 University Of Vienna Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US8697359B1 (en) 2012-12-12 2014-04-15 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
WO2014195430A1 (fr) 2013-06-05 2014-12-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Oligonucléotides antisens modifiés pour être hydrophobes comprenant un groupe cétal
WO2014195432A1 (fr) 2013-06-05 2014-12-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Oligonucléotides anti-sens modifiées par hydrophobie comprenant une chaîne alkyle triple

Non-Patent Citations (43)

* Cited by examiner, † Cited by third party
Title
"NCBI", Database accession no. NM— 004119.2
"UniProtKB", Database accession no. P36888
BELLODI C; LIDONNICI MR; HAMILTON A; HELGASON GV; SOLIERA AR; RONCHETTI M ET AL.: "Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells", J CLIN INVEST, vol. 119, 2009, pages 1109 - 1123
BENNETT J; CATOVSKY D; DANIEL M; FLANDRIN G; GALTON D; GRALNICK H; SULTAN C: "Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group", BR J HAEMATOL, vol. 33, no. 4, 1976, pages 451 - 8
BOSNJAK M; RISTIC B; ARSIKIN K; MIRCIC A; SUZIN-ZIVKOVIC V; PEROVIC V ET AL.: "Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death", PLOS ONE, vol. 9, 2014, pages e94374
BRINA D; MILUZIO A; RICCIARDI S; CLARKE K; DAVIDSEN PK; VIERO G ET AL.: "eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription", NAT COMMUN, vol. 6, 18 September 2015 (2015-09-18), pages 8261
BRINA D; MILUZIO A; RICCIARDI S; CLARKE K; DAVIDSEN PK; VIERO G; TEBALDI T; OFFENHAUSER N; ROZMAN J; RATHKOLB B: "eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription", NAT COMMUN, vol. 6, 2015, pages 8261
CECI M; GAVIRAGHI C; GORRINI C; SALA LA; OFFENHAUSER N; MARCHISIO PC; BIFFO S: "Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly", NATURE, vol. 426, no. 6966, 2003, pages 579 - 84, XP055018683, DOI: doi:10.1038/nature02160
CLEMENT LARRUE ET AL: "Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells", 18 August 2015 (2015-08-18), XP055450965, Retrieved from the Internet <URL:http://www.bloodjournal.org/content/bloodjournal/127/7/882.full.pdf> [retrieved on 20180214], DOI: 10.1182/blood-2015-05- *
COLECCHIA D; ROSSI M; SASDELLI F; SANZONE S; STRAMBI A; CHIARIELLO M: "MAPK15 mediates BCR-ABL1-induced autophagy and regulates oncogene-dependent cell proliferation and tumor formation", AUTOPHAGY, vol. 11, 2015, pages 1790 - 802
CORAZZARI M; RAPINO F; CICCOSANTI F; GIGLIO P; ANTONIOLI M; CONTI B ET AL.: "Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma", CELL DEATH DIFFER, vol. 22, 2015, pages 946 - 958
DOHNER H; WEISDORF DJ; BLOOMFIELD CD: "Acute myeloid leukemia", N ENGL J MED, vol. 373, 2015, pages 1136 - 1152
FM ABU-DUHIER; GOODEVE AC; WILSON GA ET AL.: "FLT3 internal tandem duplication mutations in adult acute myeloid leukemia define a high risk group", BRITISH JOURNAL OF HAEMATOLOGY, vol. 11, no. 1, 2000, pages 190 - 195
GALLOGLY MM; LAZARUS HM: "Midostaurin: an emerging treatment for acute myeloid leukemia patients", J BLOOD MED, vol. 7, 2016, pages 73 - 83
GAMMOH N; LAM D; PUENTE C; GANLEY I; MARKS PA; JIANG X: "Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death", PROC NATL ACAD SCI U S A, vol. 109, 2012, pages 6561 - 6565, XP055124669, DOI: doi:10.1073/pnas.1204429109
GUO JY; CHEN HY; MATHEW R; FAN J; STROHECKER AM; KARSLI-UZUNBAS G ET AL.: "Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis", GENES DEV, vol. 25, 2011, pages 460 - 470
H KIYOI; M TOWATARI; S YOKOTA: "Internal Tandem duplication of the FLT3 gene is a novel modality of elongation mutation, which causes constitutive activation of the product", LEUKEMIA, vol. 12, 1998, pages 1333 - 1337
H KIYOI; T NAOE; S YOKOTA: "Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho", LEUKEMIA, vol. 11, 1997, pages 1447 - 1452
H KIYOI; T NAOE; Y NAKANO ET AL.: "Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia", BLOOD, vol. 93, 1999, pages 3074 - 3080, XP002637536
HOPE ET AL., MOLECULAR MEMBRANE BIOLOGY, vol. 15, 1998, pages 1
ITTIG D ET AL., NUCLEIC ACIDS RES, vol. 32, 2004, pages 346 - 353
ITTIG D ET AL.: "Coll. Symp. Series, Hocec, M.", vol. 1, 2005, ACADEMY OF SCIENCES OF THE CZECH REPUBLIC, pages: 21 - 26
IVANOVA ET AL., OLIGONUCLEOTIDES, vol. 17, 2007, pages 54 - 65
KAYSER SL; SCHLENK RF; LONDONO MC; BREITENBUECHER F; WITTKE K; DU J; GRONER S ET AL.: "Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome", BLOOD, vol. 114, 2009, pages 2386 - 2392
LARRUE C; SALAND E; BOUTZEN H; VERGEZ F; DAVID M; JOFFRE C ET AL.: "Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells", BLOOD, vol. 127, 2016, pages 882 - 892
LEWIS ET AL., PROC. NATL. ACAD. SCI. USA, vol. 93, 1996, pages 3176
MARIA LYNGAAS TORGERSEN ET AL: "Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells", 22 August 2013 (2013-08-22), XP055451293, Retrieved from the Internet <URL:http://www.bloodjournal.org/content/bloodjournal/122/14/2467.full.pdf> [retrieved on 20180214], DOI: 10.1182/blood-2013-05- *
MITOU G; FRENTZEL J; DESQUESNES A; LE GONIDEC S; ALSAATI T; BEAU I ET AL.: "Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma", ONCOTARGET, vol. 6, 2015, pages 30149 - 30164
MOHAMMED DANY ET AL: "Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML", 18 August 2016 (2016-08-18), XP055450971, Retrieved from the Internet <URL:http://www.bloodjournal.org/content/128/15/1944.full.pdf> [retrieved on 20180214], DOI: 10.1182/blood-2016-04- *
NAKAO M; S YOKOTA; T IWAI: "Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia", LEUKEMIA, vol. 10, 1996, pages 191 1 - 1918
PAKOS-ZEBRUCKA K; KORYGA I; MNICH K; LJUJIC M; SAMALI A; GORMAN AM: "The integrated stress response", EMBO REP, vol. 17, 2016, pages 1374 - 1395
PAPAEMMANUIL E; GERSTUNG M; BULLINGER L; GAIDZIK VI; PASCHKA P; ROBERTS ND ET AL.: "Genomic Classification and Prognosis in Acute Myeloid Leukemia", N ENGL J MED, vol. 374, 2016, pages 2209 - 2221
PIYA S; KORNBLAU SM; RUVOLO VR; MU HI; RUVOLO PP; MCQUEEN T ET AL.: "Atg7 suppression enhances chemotherapeutic agent sensitivity and overcomes stroma-mediated chemoresistance in acute myeloid leukemia", BLOOD, vol. 128, 2016, pages 1260 - 1269
REBECCA VW; AMARAVADI RK: "Emerging strategies to effectively target autophagy in cancer", ONCOGENE, vol. 35, 2016, pages 1 - 11
RENNEBERG D ET AL., CHEMBIOCHEM, vol. 5, 2004, pages 1114 - 1118
RENNEBERG D ET AL., JACS, vol. 124, 2002, pages 5993 - 6002
RENNEBERG D ET AL., NUCLEIC ACIDS RES, vol. 15, no. 30, 2002, pages 2751 - 2757
S SCHNITTGER; C SCHOCH; M DUGA: "Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease", BLOOD, vol. 100, 2002, pages 59 - 66
TORGERSEN ML; ENGEDAL N; BOE SO; HOKLAND P; SIMONSEN A: "Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells", BLOOD, vol. 122, 2013, pages 2467 - 2476
VARDIMAN J W; HARRIS N L; BRUNNING R D: "The World Health Organization (WHO) classification of the myeloid neoplasms", BLOOD, vol. 100, no. 7, 2002, pages 2292 - 302, XP055458874, DOI: doi:10.1182/blood-2002-04-1199
VLASSOV ET AL., BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1197, 1994, pages 95 - 108
WHITE E: "The role for autophagy in cancer", J CLIN INVEST, vol. 125, 2015, pages 42 - 46
ZETSCHE ET AL.: "Cpfl is a Single RNA-guided Endonuclease of a Class 2 CRISPR-Cas System", CELL, vol. 163, 2015, pages 1 - 13

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11236171B2 (en) 2016-12-21 2022-02-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Human monoclonal antibodies specific for FLT3 and uses thereof

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