US20190060286A1 - Chemotherapeutic Methods - Google Patents

Chemotherapeutic Methods Download PDF

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US20190060286A1
US20190060286A1 US16/079,649 US201716079649A US2019060286A1 US 20190060286 A1 US20190060286 A1 US 20190060286A1 US 201716079649 A US201716079649 A US 201716079649A US 2019060286 A1 US2019060286 A1 US 2019060286A1
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David Tran
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University of Florida Research Foundation Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6843—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/248—IL-6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Tumor dormancy is a poorly understood and significant clinical problem.
  • a major cause of this late metastatic risk is the presence of cancer stem-like cells residing in distant organs after having spread from the primary tumor well before the tumor was treated and surgically removed. These metastatic cells, known as disseminated tumor cells (DTC), are dividing slowly and therefore highly resistant to treatment.
  • DTC disseminated tumor cells
  • lpDTCs low-proliferative, stem-like DTCs
  • the method can include administering a therapeutic effective amount of a p38 inhibitor compound or salt thereof to a human, and administering a therapeutic effective of a cytotoxic compound or salt thereof to the human.
  • FIG. 1 shows the SNAIL-TWIST1-p38 axis in cancer EMT, low proliferative DTCs, and macrometastasis.
  • FIGS. 2A-2D show transient TGFbeta induced EMT in epithelial cells.
  • SNAIL1 is only transiently expressed during initiation, suggesting that some other factor maintains EMT (A and B, and depicted in C).
  • TWIST1 level rises in late EMT (A), suggesting it as a likely candidate for maintaining EMT.
  • TWIST1 is required to maintain EMT in MCF10A cells (Ecad repression) in response to transient TGF ⁇ (4 h).
  • FIGS. 3A-F show the central role of p38 in EMT maintenance and cellular dormancy.
  • FIG. 3A show late EMT cells are growth arrested, which is dependent on TWIST1.
  • FIGS. 3B and 3C shows TWIST1 depletion in late EMT cells leads to reversal of growth arrest, a high ERK:p38 signaling ratio (i.e. low or inactive p38) and down-regulated of p53 and p21.
  • FIGS. 3D and 3E show the overexpression of TWIST1 leads to a modest reduction ERK:p38 signaling ratio (i.e. activated p38), which in turn results in profound growth arrest (p ⁇ 0.05).
  • FIG. 3F shows a diagram of the TWIST1-p38 signaling axis regulating cellular dormancy.
  • FIGS. 4A-4B show growth-arrested TWIST1 cells reactivated by p38 inhibition, which renders them more sensitive to the cytotoxic drug, paclitaxel (taxol) ( FIG. 4B ).
  • FIGS. 5A-5F show a model of cancer EMT/SNAIL1 reporter (SNAIL1-CBR).
  • FIG. 5A shows the targeting construct. The 3′ exon of SNAIL1 is fused in frame with the click beetle red luciferase (CBR), allowing for in vivo detection of SNAIL1.
  • FIGS. 5B-F show the high SNAIL1 expression in primary breast tumors ( FIG. 5B ) in SNAIL1-CBR/MMTV-NenNT mice correlates with a gross infiltrative phenotype ( FIG. 5C ), lung metastasis ( FIG. 5D ) and BM DTCs ( FIGS. 5E and 5F ).
  • FIGS. 6A-6D show the SNAIL1 requirement for breast tumor metastasis in MMTV-PyMT mice.
  • FIG. 6A show representative images of SNAIL1 IHC of sections of breast tumors isolated from MMTV-PyMT; SNAIL1 KO MMTV-PyMT. Control mice demonstrating efficient SNAIL1 deletion in SNAIL1 KO mice.
  • FIGS. 6B-D show SNAIL1 KO significantly reduced lung metastases ( FIGS. 6B and 6C ) and BM DTCs ( FIG. 6D ).
  • FIGS. 7A-7D show the SNAIL1-TWIST1-p38 axis intact in ErvB2-induced mouse breast cancer model.
  • FIG. 7A shows SNAIL1 is expressed in the primary tumor and associated with EMT changes.
  • FIG. 7B SNAIL1 is rarely detected in BM DTCs, although BM DTCs maintain the EMT phenotype (i.e. low Ecad and high vementin).
  • FIGS. 7C and 7D show TWIST1 expression and p38 activation (p-p38) are high in BM DTCs maintain the EMT phenotype 29/100 (29%) of BM DTCs has high expression of TWIST1.
  • FIGS. 8A-8B show the dormant TWIST1 + ; p-p38; BrdU-DTCs resistance to cytotoxic drugs in ErbB2-induced mouse breast cancer model.
  • FIG. 8A shows p38 inhibition (SB203085) increases BM DTC count while Taxol decreases it (*p ⁇ 0.05).
  • FIG. 8B shows that SB203085 decreases the fraction of TWIST1 + ; p-p38; BrdU ⁇ BM DTCs while Taxol enriches it, indicating that TWIST1 + ; p-p38 + ; BrdU ⁇ DTCs are chemoresistant (*p ⁇ 0.05).
  • FIGS. 9A-9B show the p38 inhibition increase the DTCs' sensitivity to cytotoxic chemotherapy.
  • DTCs-bearing PyMT-induced breast tumor mice were either untreated or treated with Taxol alone (10 mg/kg) or with SB203085 (10 ⁇ g/kg) followed by Taxol. Taxol was given IP every 3 weeks for 3 cycles. SB203085 was given IP BID starting 72 hours prior to Taxol and continuing until 72 hours after Taxol infusion. Ten mice were included in each reference group.
  • FIGS. 9A and B show the overall survival (A) and total BM DTCs (B) before and after chemo were determined.
  • FIGS. 10A-10F show the TWIST1:SNAIL1 ratio in bone marrow DTCs of human patients with clinically localized breast cancer.
  • FIGS. 10A-10F show the SNAIL1 expression in primary tumors (A), not in DTCs (B), correlates with metastasis.
  • TWIST1 expression in DTCs (D), not in primary tumor (C), correlates with metastasis.
  • FIGS. 11A-11C shows Phase 1 dose finding study of PH797804 plus carboplatin in patients with advanced metastatic ER-negative breast cancer who have exhausted all standard treatment.
  • FIGS. 11B and 11C show the dose escalation schedule (B) and timing escalation schedules (C) of PH797804.
  • the starting regimen will be PH797804 3 mg PO day starting 3 days prior to and ending 3 days after carboplatin.
  • FIG. 12 shows Phase 2, randomized, controlled, open-labeled study of adjuvant PH797804 plus carboplatin versus carboplatin alone in stage II or III TNBC with less than a pathologic complete response (pCR) and with TWIST1-positive lpDTCs. Dose and timing of PH797804 in combination with carboplatin will be per the phase 1 results.
  • pCR pathologic complete response
  • BM DTC bone marrow disseminated tumor cell
  • lpDTC low-proliferative disseminated tumor cell
  • R randomization
  • PFS progression/recurrence-free survival.
  • FIG. 13 Secreted cytokines that maintain EMT require Twist1.
  • MCF10A and A549 cells were transduced with a lentivirus expressing control or Twist1 shRNA, then treated with transient TGF ⁇ 1.
  • Conditioned media were obtained from d4 cultures and used to treat parental cells, and EMT status determined. Conditioned media from parental cells served as negative control.
  • FIGS. 14A and 14B Twist1 upregulates IL-6 in late EMT.
  • A Conditioned media were collected 4 d after transient TGFb1 treatment and cytokines determined using a 80-cytokine antibody array (RayBiotech). IL-6 was consistently upregulated in late EMT cells.
  • B Cells were infected with a lentivirus expressing control or Twist1 shRNA, and treated with transient TGFb 1. RT-PCRs were performed for indicated mRNAs. Twist1 depletion leads to the absence of IL-6 induction.
  • FIG. 15 IL6 is required for late EMT-associated p38 activation and growth arrest.
  • Cells were treated with transient TGF ⁇ 1 with or without neutralizing anti-IL6 antibody, and EMT status, p38 phosphorylation and growth determined in late EMT.
  • Anti-IL6 antibody alone or control IgG1 have no effect (not shown).
  • FIG. 16 The Twist1/p38/IL-6 Axis in Maintaining Growth Arrest in Dormant EMT Cells.
  • FIGS. 17A and 17B IL-6 inhibition significantly increases DTCs' sensitivity to carboplatin chemotherapy.
  • BM DTCs-bearing PyMT mice were untreated or treated with Control rat IgG1 followed by carboplatin or with IL-6 neutralizing monoclonal antibody (MP5-20F3) followed by carboplatin.
  • Carboplatin 120 mg/kg was given IP every 3 weeks for 3 cycles.
  • Anti-IL-6 antibody or control rat IgG1 (250 ⁇ g) was given IP once starting 72 hr prior to each carboplatin dosing and repeated once with each carboplatin dosing.
  • Kaplan-Meier estimate of overall survival (Log rank test, *, p ⁇ 0.05) (A) and total BM DTCs (2 sided T-test, **,p ⁇ 0.05) (B) before and after treatment were determined.
  • chemotherapeutic methods that can include administrating one or more p38 inhibitors and one or more cytotoxic drugs to a human in a particular sequence.
  • the chemotherapeutic method can be used to treat cancers, neoplasms, growths, and/or tumors. Without wanting to be bound by theory, it is believed that this chemotherapeutic method can acutely bring lpDTCs out of quiescence by inhibiting their p38 pathway, which in turn reactivates the lpDTCs' sensitivity to cytotoxic drugs.
  • the p38 inhibitor and the cytotoxic drug can be administered simultaneously or sequentially.
  • the p38 inhibitor can be administered before and the cytotoxic drug, or, conversely, the cytotoxic drug can be administered before the p38 inhibitor.
  • the chemotherapeutic method can also be used in combination with other therapies.
  • the p38 inhibitor and the cytotoxic drug can be administered before, during, or after surgical procedure and/or radiation therapy.
  • the p38 inhibitor and the cytotoxic drug can also be administered in conjunction with other anticancer agents, non-specific or targeted.
  • the specific amount of the anticancer agent will depend on the specific agent used, the type of condition being treated or managed, the severity and stage of the condition, and the amount(s) of compounds and any optional additional active agents concurrently administered to the subject.
  • p38 (also CSBP or RK) is a serine/threonine mitogen-activated protein kinase (MAPK) that has been shown to regulate pro-inflammatory cytokines.
  • MAPK mitogen-activated protein kinase
  • P38 functions by phosphorylating downstream substrates that include other kinases and transcription factors.
  • Agents that inhibit p38 kinase have been shown to block the production of cytokines including but not limited to TNF- ⁇ , IL-6, IL-8 and IL-1 ⁇ in vitro and in vivo models. See, e.g., Adams, J. L., et al., Progress in Medicinal Chemistry, 38: 1-60 (2001).
  • the p38 inhibitor can include, but is not limited to: PH797804 (3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide); RWJ 67657 (4-[4-(4-Fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol); SCIO 469 (6-Chloro-5-[[(2R,5S)-4-[(4-fluorophenyl)methyl]-2,5-dimethyl-1-piperazinyl]carbonyl]-N,N,1-trimethyl- ⁇ -oxo-1H-Indole-3-acetamide); EO 1428
  • any of the above-provided specific p38 inhibiting compounds, as well as further compounds exhibiting p38 inhibiting activity, may be disclosed in additional documents.
  • any p38 inhibiting compound disclosed in any of the following documents may be used. All of the following documents are incorporated herein by reference in their entirety: Foster M L and Halley F S, Drug News Perspect. (2000) 13:488-497; Newton R and Holden N, Biodrugs (2003) 17: 113-129; Boehm J C and Adams J L, Expert Opin. Ther. Patents (2000) 10: 25-37; Jackson P F and Bullington J L, Curr. Top. Med. Chem. (2002) 2:1011-1020; Adams J L, et al., Bioorg. Med. Chem. Lett.
  • the p38 inhibitor is an inhibitor of the IL-6 pathway.
  • An inhibitor of the IL-6 pathway can be, for example, an IL-6 inhibitor or an IL-6 receptor (IL-6R) inhibitor.
  • An IL-6 or IL-6R inhibitor can be an inhibitor of activity or expression of IL-6 or IL-6R.
  • an embodiment of the invention provides a method to treat cancers, neoplasms, growths, and/or tumors by administering an inhibitor of the IL-6 pathway to a subject.
  • this chemotherapeutic method can acutely bring lpDTCs out of quiescence by inhibiting their p38 pathway via inhibition of the IL-6 pathway, which in turn reactivates the lpDTCs' sensitivity to cytotoxic drugs.
  • An inhibitor of IL-6 pathway inhibitor can include, but is not limited to IL-6 pathway inhibitors discussed and described in United States Patent Application publications 20150299710, 20130090480, 20110136794, 20100099675, 20080274106, 20070208065, 20070134242, 20060165696 and 20030073706 as well as U.S. Pat. Nos. 5,527,546, 5,847,103, 5,849,283, 6,420,391, 6,555,555, 6,579,860, 6,596,537, 7,521,563, 7,977,371, 8,088,817, 8,614,240, 7,977,371, 8,802,092 and 9,212,223.
  • an inhibitor of IL-6 pathway is an aptamer, for example, aptamers discussed and described in U.S. Pat. No. 9,206,429 and Gupta et al. This patent and the publication are incorporated herein by reference in their entirety.
  • the inhibitor of IL-6 pathway is (4S)-3-[(2S,3S)-3-Hydroxy-2-methyl-4-methylene-1-oxononyl]-4-(1-methylethyl)-2-oxazolidinone (LMT-28).
  • the inhibitor of IL-6 pathway is curcumin.
  • an inhibitor of the IL-6 pathway is an anti-IL-6 antibody or an IL-6 binding fragment of an anti-IL-6 antibody.
  • the anti-IL-6 antibody can be a polyclonal or a monoclonal antibody.
  • the monoclonal antibody can be a chimeric or humanized antibody.
  • the fragment of an anti-IL6 antibody can be Fab, F(ab′)2, Fv or H chain and single chain Fv (scFv) in which Fv or Fv or H chain and L chain are coupled with a suitable linker.
  • Non-limiting examples of anti-IL-6 antibodies or IL-6 binding fragment thereof include Siltuximab, Olokizumab, ALD518 (BMS-945429), C326, Sirukumab, Elsilimomab and Clazakizumab. Additional examples of anti-IL-6 antibodies or IL-6 binding fragments thereof are known to a person of ordinary skill in the art and such embodiments are within the purview of the invention.
  • an inhibitor of the IL-6 pathway is an anti-IL-6R antibody or an IL-6R binding fragment of an anti-IL-6R antibody.
  • the anti-IL-6R antibody can be a polyclonal or a monoclonal antibody.
  • the monoclonal antibody can be a chimeric or humanized antibody.
  • the fragment of an anti-IL-6R antibody can be Fab, F(ab′)2, Fv or H chain and single chain Fv (scFv) in which Fv or Fv or H chain and L chain are coupled with a suitable linker.
  • Non-limiting examples of anti-IL-6R antibodies or IL-6R binding fragment thereof include tocilizumab, sarilumab, REGN88 (SAR153191) and ALX-0061.
  • the IL-6R inhibitor is a fusion protein of IL-6R with an Fc fragment of IgG.
  • the IL-6 pathway inhibitor is soluble gp130-Fc fusion protein.
  • a therapeutic effective amount of the p38 inhibitor can be from a low of about 5 mg/day, about 10 mg/day, or about 50 mg/day, to a high of about 3,000 mg/day, about 4,000 mg/day, or about 5,000 mg/day.
  • a therapeutic effective amount of the p38 inhibitor can be from about 5 mg/day to about 5,000 mg/day, 5 mg/day to about 2,000 mg/day, about 6 mg/day to about 20 mg/day, about 15 mg/day to about 45 mg/day, about 35 mg/day to about 70 mg/day, about 55 mg/day to about 105 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 1,000 mg/day, about 190 mg/day to about 300 mg/day, about 200 mg/day to about 2,500 mg/day about 225 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 500 mg/day to about 3,500 mg/day, about 540 mg/day to about 1,000 mg/day, about
  • the cytotoxic drug can include, but is not limited to: bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, melphalan, procarbazine, streptozocin, temozolomide, asparaginase, capecitabine, cytarabine, 5-fluoro uracil, fludarabine, gemcitabine, methotrexate, pemetrexed, raltitrexed; actinomycin D, dactinomycin, bleomycin, daunorubicin, doxorubicin, doxorubicin (pegylated liposomal), epirubicin, idarubicin, mitomycin, mitoxantrone, etoposide, docetaxel, irinotecan, paclitaxel, topotecan, vinblastine, vincristine, vinorelbine; carbop
  • a therapeutic effective amount of the cytotoxic drug can be from a low of about 5 mg/day, about 10 mg/day, or about 50 mg/day, to a high of about 3,000 mg/day, about 4,000 mg/day, or about 5,000 mg/day.
  • a therapeutic effective amount of the cytotoxic drug can be from about 5 mg/day to about 5,000 mg/day, 5 mg/day to about 2,000 mg/day, about 6 mg/day to about 20 mg/day, about 15 mg/day to about 45 mg/day, about 35 mg/day to about 70 mg/day, about 55 mg/day to about 105 mg/day, about 100 mg/day to about 200 mg/day, about 100 mg/day to about 1,000 mg/day, about 190 mg/day to about 300 mg/day, about 200 mg/day to about 2,500 mg/day about 225 mg/day to about 500 mg/day, about 400 mg/day to about 600 mg/day, about 500 mg/day to about 3,500 mg/day, about 540 mg/day to about 1,000 mg/day, about
  • Suitable biologically active variants comprise one or more analogues or derivatives of the p38 inhibitors and/or the cytotoxic drug. Indeed, a single compound, may give rise to an entire family of analogues or derivatives having similar activity. Accordingly, the analogues and derivatives of such p38 inhibitors and the cytotoxic drugs, can be used.
  • the p38 inhibitors and the cytotoxic drugs may contain chiral centers, which may be either be the (R) or (S) configuration, or may comprise a mixture thereof. Accordingly, the p38 inhibitors and the cytotoxic drugs also includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers.
  • geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond.
  • Other isomers are contemplated among the compounds of the present invention.
  • the isomers may be used either in pure form or in admixture with other isomers of the compounds described herein.
  • esters, amides, salts, solvates, prodrugs, and other derivatives of the compounds of the present invention may be prepared according to methods generally known in the art, such as, for example, those methods described by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992), which is incorporated herein by reference.
  • the time between administering the p38 inhibitor and administering the cytotoxic drug can vary widely.
  • the time between administering the p38 inhibitor and administering the cytotoxic drug can be as short as 1 minute, 5 minutes, or 1 hour, to as long as 3 day, 1 week, or 2 weeks.
  • the time between administering the p38 inhibitor and administering the cytotoxic drug can be from about 1 minute to about 30 minutes, about 5 minutes to about 1 hour, 10 minutes to about 3 days, about 1 hour to about 12 hours, about 1 hour to about 1 week, 6 hours to about 1 day, 6 hours to about 2 weeks, 1 day to about 1 week, 12 hours to about 6 days, or about 1 week to about 2 weeks.
  • the cancer the human is being treated for can include, but is not limited to: breast cancer, such as triple negative breast cancer, pancreas cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, fibrosarcoma, multiple myeloma, reticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, me
  • a critical signaling pathway was identified in lpDTCs that is responsible for their quiescence and treatment resistance. This pathway consists of a circular signaling loop involving the p38 MAPK and TWIST1 proteins, both of which have been found to regulate breast cancer metastasis. It was demonstrated that the TWIST1-p38MAPK axis was required for growth arrest in lpDTCs, and that inhibiting this axis was sufficient to reactivate lpDTCs and resensitize them to cytotoxic chemotherapy.
  • TWIST1 The most likely candidate was TWIST1, as its level was inversely correlated with SNAIL1 during EMT ( FIG. 2C ). Mechanistically, it was shown earlier that SNAIL1 transcriptionally repressed TWIST1 expression during EMT initiation; however TWIST1 became upregulated in late EMT as SNAIL1 level diminished ( FIG. 2 ). To test whether TWIST1 is required to maintain EMT, several EMT factors were selectively RNAi-depleted in several normal and cancer epithelial cells, followed by treatment with physiologic transient TGF ⁇ 1. It was found that TWIST1 was uniquely required to maintain E-cadherin downregulation in late EMT (FIG. ).
  • TWIST1 may, in some manner, induce a positive feed-forward loop that enhances p38 activity while weakening ERK1/2 signaling. This circular signal feedback could then amplify and propagate the resultant growth arrest critical for EMT maintenance ( FIG. 3F ). If so, then small changes in either TWIST1 or p38 activity should have a profound impact on the severity of growth arrest.
  • TWIST1 was overexpressed so as to achieve maximal TWIST1 effect, thereby avoiding the confounding problem of added TGF ⁇ 1.
  • TWIST1 overexpression alone generated vigorous TGF ⁇ 1-independent EMT and led to 2-3 fold lower ERK:p38 signaling ratio (i.e. high p38 activity) compared to the empty vector ( FIG. 3D ).
  • This modest increase in p38 activity resulted in greatly enhanced signal output as evidenced by markedly higher rate of growth arrest in TWIST1-overexpressing cells ( FIG. 3E ).
  • TWIST1 maintains EMT by creating a low ERK:p38 signaling ratio (high p38 activity).
  • high SNAIL1 levels in primary tumors would induce EMT while high TWIST1 levels would maintain EMT in metastatic cells and possibly contribute to lpDTCs in metastatic sites ( FIG. 1 ).
  • SNAIL1-CBR click beetle red luciferase
  • mice with SNAIL1-CBR+breast tumors developed BM DTCs and lung metastasis at a much higher rate compared to those having only SNAIL1-CBR negative tumors ( FIG. 5D-F ). See id.
  • SNAIL1 was necessary for breast cancer metastasis.
  • a previously characterized floxed SNAIL1 mouse in the MMTV-PyMT model was made. Deletion of SNAIL1 in primary tumors using the MMTV-cre allele and the resultant reversal of EMT-related molecular changes were verified by IHC for SNAIL1, E-cadherin and Vimentin ( FIG. 6A ). See, e.g., Rowe, R. G., et al., Mesenchymal cells reactivate Snail 1 expression to drive three - dimensional invasion programs. The Journal of Cell Biology, 2009. 184(3): p. 399-408.
  • SNAIL1 is required for cancer EMT initiation in primary tumors and breast cancer metastasis.
  • SNAIL expression and EMT-associated molecular changes were readily detectable in multiple invasive projections in SNAIL1-CBR positive tumors, as compared to SNAIL1-CBR negative tumors.
  • SNAIL1 expression was rarely found in BM DTCs, which retained mesenchymal traits (i.e. loss of Ecad and gain of Vimentin) ( FIG. 7A-B ), indicating that SNAIL1 expression was restricted to the invasive front of primary tumors because of its main role as an EMT initiator, and that some other EMT factor(s) must have supplanted SNAIL1 in secondary organs.
  • TWIST1-positive BM DTCs nearly 80% ( 23/29) expressed activated p38 (p-p38) and 70% ( 20/29) were also growth arrested as measured by a lack of BrdU incorporation ( FIG. 7C-D ).
  • 94% ( 67/71) lacked activated p38 and 77% ( 55/71) were also actively proliferating. Therefore TWIST1-positive; p-p38-positive; BrDU-negative cells represent the fraction of true lpDTCs in these models.
  • mice were treated with either SB203085 (10 ⁇ mol/kg IP BID ⁇ 7 days) or the cytotoxic drug paclitaxel (Taxol, 10 mg/kg IP once) and measured the number of all BM DTCs and the fraction of lpDTCs (ratio of TWIST1+; p-p38+; BrdU-DTCs over total BM DTCs).
  • breast cancer mice were treated with either Taxol alone or a combination SB203085 and Taxol and measured both the number of BM DTCs and overall survival.
  • ErbB2- or PyMT-induced breast tumor mice were untreated or treated with either Taxol alone or a combination of SB203085 plus Taxol with SB203085 starting 72 hrs prior to and ending 72 hrs after each dose of Taxol ( FIG. 9 ).
  • Three 21-day cycles of chemotherapy were given.
  • Total BM DTCs were determined prior to and 1 week after treatment ended.
  • mice Both MMTV-ErbB2 and MMTV-PyMT mice were used and similar results were obtained for both mouse strains. Results from MMTV-PyMT mice, which produce TNBC, were shown in FIG. 9 . Pretreatment with SB203085 significantly reduced total BM DTCs and increased overall survival, compared to Taxol alone and untreated controls ( FIG. 9A-B ). Taken together, these results paint a coherent picture tying p38 activity to the TWIST1-dependent EMT maintenance of lpDTCs that eventually leads to early relapses in ER/PR-negative breast cancer.
  • TWIST 1 as a marker of early tumor relapse in breast cancer patients.
  • p38MAPK has been demonstrated to regulate the expression of various inflammatory mediators and, as a result, several p38 inhibitors have been developed to treat inflammatory diseases such as autoimmunity and emphysema and currently are undergoing human phase I and II clinical trials. See, e.g., MacNee, W., et al., Efficacy and safety of the oral p 38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax, 2013. 68(8): p. 738-745; Cohen, S. and R. Fleischmann, Kinase inhibitors: a new approach to rheumatoid arthritis treatment . Current Opinion in Rheumatology, 2010.
  • gamma and delta isoforms have more restricted expression and are less well understood.
  • Most human ready p38 inhibitors currently in clinical studies selectively target alpha with minimal to negligible effect on beta.
  • beta isoform cannot be ruled out by our preliminary data as playing a role in lpDTCs, especially whether there is a compensatory upregulation of beta once alpha is inhibited, it is essential to select a human ready p38 inhibitor that can inhibit both alpha and beta.
  • PH797804 a novel pyridinone inhibitor of p38, is one of the most advanced p38 inhibitors in human clinical trials.
  • PH797804 is a potent and highly selective inhibitor of alpha with IC50 of 26 nM yet retains reasonable inhibitory effect on beta (IC50 of 102 nM).
  • IC50 of 102 nM IC50 of 102 nM.
  • PH797804 was well tolerated across all 4 dose levels (0.5, 3, 6, and 10 mg PO qday). No significant severe adverse events were reported. The most common side effect was skin rash ( ⁇ 1%). It is commercially available and clinical grade PH797804 is manufactured by Pfizer.
  • Twist1-positive late EMT cells conditioned media obtained from Twist1-positive late EMT cells, but not from cells depleted of Twist1, induced EMT, suggesting that Twist1 induces changes in secreted cytokines that maintain EMT ( FIG. 13 ).
  • conditioned media from resting and late EMT cells treated with transient TGF ⁇ 1 MCF10A and A549 cells
  • cytokines known to influence p38 or EMT e.g., PDGF, TGF ⁇ 1, EGF, FGF, and IL-6
  • IL-6 was the only secreted cytokine in this array that was consistently increased in both cell lines during late EMT as compared to resting cells.
  • TGF ⁇ 1 a well-known activator of IL-6 (Yao et al., 2010), may be responsible for inducing IL-6 in late EMT as it was used earlier to induce EMT.
  • TGF ⁇ 1 was not detected in late EMT cells ( FIG. 14A ); thus IL-6 secretion in late EMT is independent of TGF ⁇ 1.
  • IL-6 is a pro-inflammatory cytokine normally secreted by T cells and macrophages.
  • IL-6 signals through the IL6 (or gp130) family of receptors, which regulates B cell differentiation and the acute phase reaction.
  • IL-6 binding induces receptor dimerization, activating the associated JAKs, which phosphorylate themselves and the receptor.
  • the phosphorylated sites on the receptor and JAKs serve as docking sites for the SH2-containing Stats, such as Stat3, and for SH2-containing proteins and adaptors that link the receptor to MAP kinases (including p38 and ERK1/2), PI3K/Akt, and other pathways.
  • IL-6 has been shown to play regulatory roles in multiple cancers including prostate cancer, multiple myeloma and metastatic cancer (Kishimoto, 2005). Importantly, IL-6 was suggested to be a critical component of an autocrine/paracrine cytokine network regulating stem-like breast cancer cells (Liu et al., 2011). Thus IL-6 is a potential candidate that mediates Twist1-dependent p38 activation and EMT maintenance.
  • Twist1 activates IL-6
  • IL-6 transcript in late EMT cells with or without Twist1 depletion was measured.
  • IL-6 upregulation in late EMT was at the transcriptional level and that Twist1 was required for IL-6 production ( FIG. 14B ).
  • an IL-6 neutralizing antibody was utilized to inactivate IL-6.
  • Anti-IL-6 antibody was sufficient to reverse late EMT-associated p38 activation and growth arrest ( FIG. 15 ), while anti-IL-6 antibody alone or control IgG1 had no effect.
  • IL-6 appears to be a critical intermediary between Twist1 and p38 ( FIG. 16 ) and thus a natural target to use to break the growth arrest cycle of low proliferative DTCs (lpDTCs) to reawaken them.
  • IL-6 represent a critical signaling intermediary between Twist1 and p38MAPK in the Twist1-dependent EMT maintenance of lpDTCs in breast cancer.
  • Neutralization IL-6 profoundly reversed the growth arrest phenotype of lpDTCs, effectively re-sensitizing them to killing by cytotoxic drugs and making it possible to eliminate these lpDTCs—the main source of early relapses in high-risk breast cancer.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 0-20%, 0 to 10%, 0 to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
  • compositions containing amounts of ingredients where the terms “about” or “approximately” are used contain the stated amount of the ingredient with a variation (error range) of 0-10% around the value (X ⁇ 10%).
  • ranges are stated in shorthand, so as to avoid having to set out at length and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range.
  • a range of 0.1-1.0 represents the terminal values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges encompassed within 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc.
  • Values having at least two significant digits within a range are envisioned, for example, a range of 5-10 indicates all the values between 5.0 and 10.0 as well as between 5.00 and 10.00 including the terminal values.
  • an optional component in a system means that the component may be present or may not be present in the system.
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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190060286A1 (en) 2016-02-29 2019-02-28 University Of Florida Research Foundation, Incorpo Chemotherapeutic Methods
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GB201721793D0 (en) * 2017-12-22 2018-02-07 Hvivo Services Ltd Methods and compunds for the treatment or prevention of hypercytokinemia and severe influenza
AU2019238197A1 (en) * 2018-03-20 2020-09-10 Dana-Farber Cancer Institute, Inc. Compositions and methods for cancer treatment
CA3119341A1 (fr) * 2018-11-16 2020-05-22 Neoimmunetech, Inc. Methode de traitement d'une tumeur au moyen de l'association de la proteine il-7 et d'un inhibiteur de point de controle immunitaire

Family Cites Families (185)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9816837D0 (en) 1998-08-04 1998-09-30 Zeneca Ltd Amide derivatives
WO1994025036A1 (fr) 1993-04-30 1994-11-10 Chugai Seiyaku Kabushiki Kaisha Inhibiteur d'expression contenant un derive d'oligonucleotide antisens, agissant contre le recepteur de l'interleukine-6 humain
US5527546A (en) 1994-08-10 1996-06-18 Bayer Corporation Human interleukin 6 inhibitor
IT1274782B (it) 1994-12-14 1997-07-24 Angeletti P Ist Richerche Bio Metodo per selezionare superagonisti, antagonisti e superantagonisti di ormoni del cui complesso recettoriale fa parte gp 130
US6596537B1 (en) 1994-12-16 2003-07-22 Chugai Seiyaku Kabushiki Kaisha Human interleukin-6 receptor expression inhibitor
US6147080A (en) 1996-12-18 2000-11-14 Vertex Pharmaceuticals Incorporated Inhibitors of p38
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
GB9713726D0 (en) 1997-06-30 1997-09-03 Ciba Geigy Ag Organic compounds
KR20010020570A (ko) 1997-06-30 2001-03-15 자끄 사비나 다세포 진핵 생물 세포중으로 개선된 핵산 전달방법 및이를 위한 콤비네이션
DK1017378T3 (da) 1997-09-23 2003-03-17 Astrazeneca Ab Amidderivater til behandling af sygdomme medieret af cytokiner
EP1067128A4 (fr) 1998-04-01 2001-11-21 Ono Pharmaceutical Co Derives de thiophene condenses et medicaments contenant ceux-ci comme principe actif
US6316466B1 (en) 1998-05-05 2001-11-13 Syntex (U.S.A.) Llc Pyrazole derivatives P-38 MAP kinase inhibitors
US6589954B1 (en) 1998-05-22 2003-07-08 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
WO2000007991A1 (fr) 1998-08-04 2000-02-17 Astrazeneca Ab Derives d'amides utiles comme inhibiteurs de la production de cytokines
ES2221426T3 (es) 1998-08-20 2004-12-16 Smithkline Beecham Corporation Nuevos compuestos de triazol sustituidos.
CN1261098C (zh) 1998-08-28 2006-06-28 西奥斯股份有限公司 p38－α激酶的抑制剂
CA2337755C (fr) 1998-09-18 2008-07-29 Vertex Pharmaceuticals Incorporated Inhibiteurs de p38
AR023659A1 (es) 1998-09-18 2002-09-04 Vertex Pharma Un compuesto inhibidor de p38, una composicion farmaceutica que lo comprende y el uso de dicha composicion en el tratamiento y prevencion de estados patologicos
DE69912823T2 (de) 1998-09-25 2004-09-23 Astrazeneca Ab Benzamid-derivate und ihre verwendung als cytokine inhibitoren
IL142257A0 (en) 1998-10-01 2002-03-10 Astrazeneca Ab Amide derivatives, process for their preparation, compositions containing them and use thereof in the manufacture of a medicament for the treatment of cytokine-mediated diseases
ATE258055T1 (de) 1998-11-04 2004-02-15 Smithkline Beecham Corp Pyridin-4-yl oder pyrimidin-4-yl substituierte pyrazine
DE69915862T2 (de) 1998-11-20 2004-08-05 G.D. Searle Llc Verfahren zur herstellung 5-substituierter pyrazole unter verwendung von dithietane
DE69903976T2 (de) 1998-12-16 2003-07-24 Aventis Pharma Ltd Heteroaryl-zyklische acetale
CN1217666C (zh) 1998-12-25 2005-09-07 东丽株式会社 白介素－6产生抑制剂
DE69926542T2 (de) 1998-12-25 2006-04-27 Teikoku Hormone Mfg. Co., Ltd. Aminopyrazolderivate
JP2002534385A (ja) 1999-01-08 2002-10-15 スミスクライン・ビーチャム・コーポレイション 新規化合物
EP2298311B1 (fr) 1999-01-13 2012-05-09 Bayer HealthCare LLC Urées de diphényle à substitution omega-carboxyaryle en tant qu'inhibiteurs de la p38 kinase
US20020065296A1 (en) 1999-01-13 2002-05-30 Bayer Corporation Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
WO2000055120A1 (fr) 1999-03-17 2000-09-21 Astrazeneca Ab Derives amides
EP1163237B1 (fr) 1999-03-17 2004-05-06 AstraZeneca AB Derives amides
GB9906566D0 (en) 1999-03-23 1999-05-19 Zeneca Ltd Chemical compounds
CO5170501A1 (es) 1999-04-14 2002-06-27 Novartis Ag AZOLES SUSTITUIDOS UTILES PARA EL TRATAMIENTO DE ENFERMEDADES MEDIADAS POR TNFa eIL-1 Y ENFERMEDADES DEL METABOLISMO OSEO
ES2275500T3 (es) 1999-04-23 2007-06-16 Takeda Pharmaceutical Company Limited Compuestos de 5-piridil-1,3-azol, procedimiento para su produccion y uso de los mismos.
HUP0201261A3 (en) 1999-05-21 2003-12-29 Scios Inc Sunnyvale Indole-type derivatives as inhibitors of p38 kinase and pharmaceutical compositions containing them
WO2001010865A1 (fr) 1999-08-06 2001-02-15 Takeda Chemical Industries, Ltd. INHIBITEURS DE p38MAP KINASE
EP1224185B1 (fr) 1999-10-27 2005-11-30 Novartis AG Composes thiazole et imidazo [4,5-b] pyridine et leur utilisation pharmaceutique
SK9892001A3 (en) 1999-11-10 2002-04-04 Ortho Mcneil Pharm Inc Substituted 2-aryl-3-(heteroaryl)-imidazo[1,2-a]pyrimidines, and related pharmaceutical compositions and methods
US7053098B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-Dihydro-(1H) quinazolin-2-one compounds as CSBP/P38 kinase inhibitors
JP2003528043A (ja) 1999-11-23 2003-09-24 スミスクライン・ビーチャム・コーポレイション ＣＳＢＰ／ｐ３８キナーゼ阻害剤としての３，４‐ジヒドロ−（１Ｈ）キナゾリン−２−オン化合物
ATE281439T1 (de) 1999-11-23 2004-11-15 Smithkline Beecham Corp 3,4-dihydro-(1h)chinazolin-2-on-verbindungen als csbp/p38-kinase-inhibitoren
AU1626001A (en) 1999-11-23 2001-06-04 Smithkline Beecham Corporation 3,4-dihydro-(1h)-quinazolin-2-ones and their use as csbp/p38 kinase inhibitors
US6849639B2 (en) 1999-12-14 2005-02-01 Amgen Inc. Integrin inhibitors and their methods of use
CN1615873A (zh) 1999-12-24 2005-05-18 阿文蒂斯药物有限公司 氮杂吲哚类化合物
EP1246823A1 (fr) 1999-12-28 2002-10-09 Pharmacopeia, Inc. Composes de pyrimidine et de triazine presentant une activite inhibant la kinase
DE10001166A1 (de) 2000-01-13 2001-07-19 Merckle Gmbh Anellierte Pyrrolverbindungen, diese enthaltende pharmazeutische Mittel und deren Verwendung
DE10004157A1 (de) 2000-02-01 2001-08-02 Merckle Gmbh Chem Pharm Fabrik 4-Pyridyl-und 2,4-Pyrimidinyl-substituierte Pyrrolderivate und ihre Anwendung in der Pharmazie
WO2001057018A1 (fr) 2000-02-02 2001-08-09 Abbott Laboratories Inhibiteurs d'azaazulene de la p38 map kinase ou du tnf-alpha
WO2001060816A1 (fr) 2000-02-17 2001-08-23 Amgen Inc. Inhibiteurs de kinases
MY141144A (en) 2000-03-02 2010-03-15 Smithkline Beecham Corp 1, 5-disubstituted-3,4-dihydro-1h-pyrimido 4,5-dipyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
MXPA02009319A (es) 2000-03-22 2003-03-12 Vertex Pharma Inhibidores de p38.
EP1268474A2 (fr) 2000-03-30 2003-01-02 Takeda Chemical Industries, Ltd. Composes de 1,3-thiazole substitues, production et utilisation desdits composes
KR20030001551A (ko) 2000-05-22 2003-01-06 레오 파마 에이/에스 ＩＬ-1β 및 ＴＮＦ-α 억제제로서의 벤조페논
US6645990B2 (en) 2000-08-15 2003-11-11 Amgen Inc. Thiazolyl urea compounds and methods of uses
PE20020506A1 (es) 2000-08-22 2002-07-09 Glaxo Group Ltd Derivados de pirazol fusionados como inhibidores de la proteina cinasa
JP2004511542A (ja) 2000-10-19 2004-04-15 スミスクライン・ビーチャム・コーポレイション 煙の吸入の治療のためのｐ３８阻害剤の使用
WO2002060869A2 (fr) 2000-10-19 2002-08-08 Smithkline Beecham Corporation Utilisation d'inhibiteurs p38 pour le traitement de toux inflammatoire
CA2426654C (fr) 2000-10-23 2010-12-21 Smithkline Beecham Corporation Nouveaux composes
CA2429628A1 (fr) 2000-11-17 2002-05-23 Bristol-Myers Squibb Company Methodes de traitement des pathologies liees a la kinase p38 et composes de pyrrolotiazine utilises en tant qu'inhibiteurs de la kinase
CA2429258A1 (fr) 2000-11-20 2002-06-13 Scios Inc. Inhibiteurs du type piperidine/piperazine de la kinase p38
WO2002042292A2 (fr) 2000-11-20 2002-05-30 Scios Inc. Inhibiteurs de la kinase p38
EP1345603A4 (fr) 2000-12-20 2004-09-08 Merck & Co Inc Agents inhibiteurs de p38 kinase (halo-benzo carbonyl)heterocyclo- fusionnes phenyl
US7102009B2 (en) 2001-01-12 2006-09-05 Amgen Inc. Substituted amine derivatives and methods of use
US20030134836A1 (en) 2001-01-12 2003-07-17 Amgen Inc. Substituted arylamine derivatives and methods of use
US6995162B2 (en) 2001-01-12 2006-02-07 Amgen Inc. Substituted alkylamine derivatives and methods of use
US7105682B2 (en) 2001-01-12 2006-09-12 Amgen Inc. Substituted amine derivatives and methods of use
US6878714B2 (en) 2001-01-12 2005-04-12 Amgen Inc. Substituted alkylamine derivatives and methods of use
GB0119435D0 (en) 2001-02-15 2001-10-03 Aventis Pharm Prod Inc Method of treating of demyelinating diseases or conditions
DE10107683A1 (de) 2001-02-19 2002-08-29 Merckle Gmbh Chem Pharm Fabrik 2-Thio-substituierte Imidazolderivate und ihre Verwendung in der Pharmazie
BR0207957A (pt) 2001-03-09 2004-02-25 Pfizer Prod Inc Compostos antiinflamatórios de benzimidazol
AP2002002463A0 (en) 2001-03-09 2002-06-30 Pfizer Prod Inc Novel triazolo-pyrimides anti-inflammatory compounds.
GB2373245A (en) 2001-03-12 2002-09-18 Bayer Ag Pyridinyl pyrazoles and their use for the treatment of COPD
GB0107368D0 (en) 2001-03-23 2001-05-16 Novartis Ag Organic compounds
DE60205974T2 (de) 2001-04-04 2006-06-29 Pfizer Products Inc., Groton Neue Benzotriazole mit entzündungshemmender Wirkung
AU2002338286A1 (en) 2001-04-10 2002-10-28 Leo Pharma A/S Novel aminophenyl ketone derivatives
US6881737B2 (en) 2001-04-11 2005-04-19 Amgen Inc. Substituted triazinyl acrylamide derivatives and methods of use
US6864255B2 (en) 2001-04-11 2005-03-08 Amgen Inc. Substituted triazinyl amide derivatives and methods of use
JP2004536057A (ja) 2001-05-11 2004-12-02 バーテックス　ファーマシューティカルズ　インコーポレイテッド ｐ３８インヒビターとして使用する２，５−二置換ピリジン、ピリミジン、ピリダジンおよび１，２，４−トリアジンの誘導体
GB0115109D0 (en) 2001-06-21 2001-08-15 Aventis Pharma Ltd Chemical compounds
CA2450555A1 (fr) 2001-06-25 2003-01-03 Merck & Co., Inc. Composes d'heteroaryle fondus (pyrimidyle)(phenyle) substitues inhibiteurs de p38 et de la kinase pkg
CA2451128A1 (fr) 2001-06-26 2003-01-09 Bristol-Myers Squibb Company Inhibiteurs n-heterocycliques d'expression tnf-alpha
GB0117506D0 (en) 2001-07-18 2001-09-12 Bayer Ag Imidazopyridinones
US6939874B2 (en) 2001-08-22 2005-09-06 Amgen Inc. Substituted pyrimidinyl derivatives and methods of use
US7115617B2 (en) 2001-08-22 2006-10-03 Amgen Inc. Amino-substituted pyrimidinyl derivatives and methods of use
DE60207273T2 (de) 2001-08-30 2006-07-20 F. Hoffmann-La Roche Ag Aminopyrrolverbindungen als entzündungshemmende Wirkstoffe
ATE421877T1 (de) 2001-09-17 2009-02-15 Johnson & Johnson Consumer Verwendung von totarol zur behandlung von pruritus
US6821971B2 (en) 2001-09-20 2004-11-23 The Procter & Gamble Company Fused pyrazolone compounds which inhibit the release of inflammatory cytokines
GB0124848D0 (en) 2001-10-16 2001-12-05 Celltech R&D Ltd Chemical compounds
GB0124941D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124933D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124931D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124936D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124938D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124932D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124934D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124939D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124928D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
IL160874A0 (en) 2001-10-22 2004-08-31 Tanabe Seiyaku Co 4-imidazolin-2-one derivatives
US6921762B2 (en) 2001-11-16 2005-07-26 Amgen Inc. Substituted indolizine-like compounds and methods of use
HUP0500027A2 (hu) 2001-11-22 2005-04-28 Ono Pharmaceutical Co., Ltd. Piperidin-2-on-származékok és hatóanyagként ezeket tartalmazó gyógyászati készítmények
JP2005516955A (ja) 2001-12-21 2005-06-09 バイエル・ヘルスケア・アクチェンゲゼルシャフト アロイル・ピリジノン化合物
MXPA04007838A (es) 2002-02-12 2004-10-15 Smithkline Beecham Corp Derivados de nicotamida utiles como inhibidores p38.
GEP20063937B (en) 2002-02-14 2006-10-10 Pharmacia Corp Substituted pyridinones as modulators of p38 map kinase
CA2477721A1 (fr) 2002-03-07 2003-09-12 F. Hoffmann-La Roche Ag Pyridine et pyrimidine bicycliques, inhibitrices de la p38 kinase
US20060046999A1 (en) 2002-03-14 2006-03-02 Cristina Alonso-Alija Monocyclic aroylpyridinones as antiinflammatory agents
US20040122008A1 (en) 2002-09-05 2004-06-24 Protter Andrew A. Treatment of pain by inhibition of p38 MAP kinase
GB0206860D0 (en) 2002-03-22 2002-05-01 Glaxo Group Ltd Compounds
WO2003082871A1 (fr) 2002-04-03 2003-10-09 F. Hoffmann-La Roche Ag Composes imidazo-fusionnes
AR039241A1 (es) 2002-04-04 2005-02-16 Biogen Inc Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos
EP1495016A2 (fr) 2002-04-09 2005-01-12 Astex Technology Limited Composes heterocycliques et leur utilisation comme modulateurs de la kinase p38 map
US20030225089A1 (en) 2002-04-10 2003-12-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors
CN1646131A (zh) 2002-04-19 2005-07-27 史密丝克莱恩比彻姆公司 新化合物
PL373371A1 (en) 2002-04-23 2005-08-22 Bristol-Myers Squibb Company Aryl ketone pyrrolo-triazine compounds useful as kinase inhibitors
GB0209891D0 (en) 2002-04-30 2002-06-05 Glaxo Group Ltd Novel compounds
WO2003097062A1 (fr) 2002-05-13 2003-11-27 Merck & Co., Inc. Imidazopyridines phenyle substituees et benzimidazoles phenyle substitues
US7119111B2 (en) 2002-05-29 2006-10-10 Amgen, Inc. 2-oxo-1,3,4-trihydroquinazolinyl derivatives and methods of use
PE20040522A1 (es) 2002-05-29 2004-09-28 Novartis Ag Derivados de diarilurea dependientes de la cinasa de proteina
US20030231811A1 (en) 2002-06-07 2003-12-18 Hodson Jay D. Internally scored film, package and methods of making the same
AU2003238915B2 (en) 2002-06-11 2008-02-21 Merck & Co., Inc. (halo-benzo carbonyl)heterobicyclic p38 kinase inhibiting agents
US7307088B2 (en) 2002-07-09 2007-12-11 Amgen Inc. Substituted anthranilic amide derivatives and methods of use
GB0217757D0 (en) 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
DE60316581T2 (de) 2002-08-06 2008-07-03 F. Hoffmann-La Roche Ag 6-alkoxypyridopyrimidine als inhibitoren der p-38-map-kinase
JP2006504667A (ja) 2002-08-08 2006-02-09 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド 炎症過程に関与するサイトカインの抑制剤としてのフッ素化フェニル−ナフタレニル−尿素化合物
EP1554272B1 (fr) 2002-08-09 2006-10-25 Eli Lilly And Company Benzimidazoles et benzothiazoles utilises comme inhibiteurs de la map kinase
GB0218800D0 (en) 2002-08-13 2002-09-18 Celltech R&D Ltd Chemical compounds
US7005523B2 (en) 2002-08-30 2006-02-28 Pfizer Inc. Cycloalkyl-[4-(trifluorophenyl)-oxazol-5yl]-triazolo-pyridines
US7012143B2 (en) 2002-08-30 2006-03-14 Dombroski Mark A Cycloalkyl-[4-(difluorophenyl)-oxazol-5-yl]-triazolo-pyridines
PA8579601A1 (es) 2002-08-30 2004-05-07 Pfizer Prod Inc Compuestos antiinflamatorios de di y trifloruro-triazolo-piridinas
US7037923B2 (en) 2002-08-30 2006-05-02 Pfizer, Inc. Alkyl-[4-(trifluorophenyl)-oxazol-5-yl]-triazolo-pyridines
AU2003268464A1 (en) 2002-09-03 2004-03-29 Scios Inc. INDOLE-TYPE DERIVATIVES AS INHIBITORS OF p38 KINASE
ATE355839T1 (de) 2002-09-09 2007-03-15 Amgen Inc 1,4,5-substituierte 1,2-dihydro-pyrazol-3-one and 3-alkoxy-1h-pyrazole derivate als tnf-alpha und interleukin senkende wirkstoffe zur behandlung von entzündungen
US7115644B2 (en) 2002-09-13 2006-10-03 Boehringer Ingelheim Pharmaceuticals Inc. Heterocyclic compounds
AU2003268155A1 (en) 2002-09-19 2004-04-08 Eli Lilly And Company Methods of inhibiting tgf beta with substituted pyrazoles
GB0222743D0 (en) 2002-10-01 2002-11-06 Celltech R&D Ltd Chemical compounds
WO2004032874A2 (fr) 2002-10-09 2004-04-22 Scios Inc. Derives d'azaindole utilises en tant qu'inhibiteurs de la kinase p38
KR20050075028A (ko) 2002-11-18 2005-07-19 에프. 호프만-라 로슈 아게 다이아지노피리미딘
US7309701B2 (en) 2002-11-19 2007-12-18 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them
US7462613B2 (en) 2002-11-19 2008-12-09 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them
KR20050111314A (ko) 2002-12-20 2005-11-24 암젠 인코포레이션 천식 및 알레르기성 염증 조절제들
US7144911B2 (en) 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
ATE479667T1 (de) 2003-02-06 2010-09-15 Bristol Myers Squibb Co Als kinaseinhibitoren geeignete verbindungen auf thiazolylbasis
PL378111A1 (pl) 2003-02-14 2006-03-06 Smithkline Beecham Corporation Nowe związki
CN100340294C (zh) 2003-02-24 2007-10-03 中外制药株式会社 含有白介素6拮抗剂的脊髓损伤治疗剂
DE602004029145D1 (de) 2003-02-27 2010-10-28 Palau Pharma Sa Pyrazolopyridin-derivate
US7531553B2 (en) 2003-03-21 2009-05-12 Amgen Inc. Heterocyclic compounds and methods of use
US20070167621A1 (en) 2003-04-03 2007-07-19 Pharmacia Corporation Substituted pyrimidinones
GB0308466D0 (en) 2003-04-11 2003-05-21 Novartis Ag Organic compounds
ES2279361T3 (es) 2003-04-16 2007-08-16 F. Hoffmann-La Roche Ag Derivados de (6-(fenoxi)-pirido-3,4-dipirimidin-2-il)-amina como inhibidores de p38 kinasa para el tratamiento de estados inflamatorios tal como artritis reumatoide.
MXPA05011103A (es) 2003-04-16 2005-12-12 Hoffmann La Roche Compuestos de quinazolina.
GB0320244D0 (en) 2003-05-06 2003-10-01 Aventis Pharma Inc Pyrazoles as inhibitors of tumour necrosis factor
BRPI0410905A (pt) 2003-06-03 2006-06-27 Novartis Ag inibidores de p-38
US7381841B2 (en) 2003-08-22 2008-06-03 Sanofi-Aventis Deutschland Gmbh Pentafluorosulfanylphenyl-substituted benzoylguanidines, processes for their preparation, their use as medicament or diagnostic aid, and medicament comprising them
US7320992B2 (en) 2003-08-25 2008-01-22 Amgen Inc. Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use
US7390820B2 (en) 2003-08-25 2008-06-24 Amgen Inc. Substituted quinolinone derivatives and methods of use
EP1690550B1 (fr) 2003-10-17 2012-08-08 Chugai Seiyaku Kabushiki Kaisha Agent de traitement de mesotheliome
EP1685131B1 (fr) 2003-11-13 2007-03-07 F. Hoffmann-La Roche AG Pyrido-7-pyrimidin-7-ones substitues hydroxyalkyle
ES2339670T3 (es) 2003-12-23 2010-05-24 Novartis Ag Inhibidores heterociclicos biciclicos de la quinasa p-38.
CA2553923A1 (fr) 2004-01-22 2005-08-04 Amgen Inc. Composes heterocycliques substitues et leurs methodes d'utilisation
AU2005207946A1 (en) 2004-01-23 2005-08-11 Amgen Inc. Quinoline quinazoline pyridine and pyrimidine counds and their use in the treatment of inflammation angiogenesis and cancer
MXPA06009462A (es) 2004-02-27 2007-03-15 Hoffmann La Roche Derivados pirazolo heteroaril fusionados.
DE102004010207A1 (de) 2004-03-02 2005-09-15 Aventis Pharma S.A. Neue 4-Benzimidazol-2-yl-pyridazin-3-on-Derivate
EP1598348A1 (fr) 2004-05-18 2005-11-23 Aventis Pharma Deutschland GmbH Dérivés de pyridazinone comme inhibiteurs de CDK2
US7507748B2 (en) 2004-07-22 2009-03-24 Amgen Inc. Substituted aryl-amine derivatives and methods of use
EP1787986A4 (fr) 2004-08-10 2007-08-22 Shizuoka Coffein Co Ltd Dérivé d"acide hydroxamique et médicament comportant celui-ci comme ingrédient actif
AU2005273612B2 (en) 2004-08-12 2010-10-14 Pfizer Inc. Triazolopyridinylsulfanyl derivatives as p38 map kinase inhibitors
EP1786811A2 (fr) 2004-08-18 2007-05-23 Pharmacia & Upjohn Company LLC Nouveaux compose de triazolopyridine
EP1781655A2 (fr) 2004-08-18 2007-05-09 Pharmacia & Upjohn Company LLC Nouveaux composes de triazolopyridine pour le traitement d'inflammation
KR20070073791A (ko) 2004-10-18 2007-07-10 암젠 인코포레이티드 티아디아졸 화합물 및 이의 사용방법
BRPI0608739A2 (pt) 2005-02-28 2011-03-15 Merckle Gmbh composto, composição farmacêutica, uso de pelo menos um dos compostos, e, método para tratar distúrbios associados com um enfraquecimento do sistema imune
MX2007012951A (es) 2005-03-25 2008-01-11 Glaxo Group Ltd Procedimiento para preparar derivados de pirido[2,3-d] pirimidin-7-ona y 3,4-dihidropirimidino[4,5-d]pirimidin-2(1h)-ona.
JP2008535822A (ja) 2005-03-25 2008-09-04 グラクソ グループ リミテッド 新規化合物
WO2007023114A1 (fr) 2005-08-25 2007-03-01 F. Hoffmann-La Roche Ag Inhibiteurs de p38 map kinases et procedes d'utilisation de ces derniers
BRPI0706621A2 (pt) 2006-01-18 2011-04-05 Amgen Inc composto, composição farmacêutica, métodos para tratar um distúrbio mediado por quinase em um mamìfero e para tratar um distúrbio relacionado com a proliferação em um mamìfero, e , uso do composto
EP1987022A1 (fr) 2006-02-10 2008-11-05 Pfizer Products Inc. Derives pyridinone-pyrazole-uree et pyrimidinone-pyrazole-uree
EP1894925A1 (fr) 2006-08-24 2008-03-05 Merckle Gmbh Derivés d'imidazole ayant une activité anti-inflammatoire
CN101558072A (zh) 2006-12-19 2009-10-14 霍夫曼-拉罗奇有限公司 吡唑并[3,4-d]嘧啶p38map激酶抑制剂
EP2116530B1 (fr) 2007-02-26 2012-11-14 Santen Pharmaceutical Co., Ltd Nouveau dérivé de pyrrole ayant un groupe uréide et un groupe aminocarbonyle comme substituants
WO2008104473A2 (fr) 2007-02-28 2008-09-04 F. Hoffmann-La Roche Ag Inhibiteurs de kinase et procédés d'utilisation de ces derniers
WO2008150899A1 (fr) * 2007-05-29 2008-12-11 Emory University Thérapies combinées pour le traitement du cancer et des maladies inflammatoires
RU2500669C2 (ru) 2008-08-25 2013-12-10 Сантен Фармасьютикал Ко., Лтд. Новое производное пиррола, имеющее в качестве заместителей уреидогруппу, аминокарбонильную группу и бициклическую группу, у которых могут быть заместители
US9212223B2 (en) 2008-11-25 2015-12-15 Alderbio Holdings Llc Antagonists of IL-6 to prevent or treat thrombosis
KR101372721B1 (ko) 2010-06-18 2014-03-14 이화여자대학교 산학협력단 Ｉｎｔｅｒｌｅｕｋｉｎ―６ 억제 작용을 갖는 신규한 벤즈옥사졸 유도체, 이의 제조 방법 및 이를 포함하는 약학적 조성물
WO2013119923A1 (fr) * 2012-02-09 2013-08-15 The Regents Of The University Of Michigan Cellules souches cancéreuses à différents stades
AU2012395641B2 (en) 2012-11-29 2019-10-03 Sbi Biotech Co., Ltd. Inhibitory oligonucleotide and use thereof
US20190060286A1 (en) 2016-02-29 2019-02-28 University Of Florida Research Foundation, Incorpo Chemotherapeutic Methods

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