WO2017087818A1 - Double inhibiteur de kinase p38/src et leur utilisation comme agents thérapeutiques - Google Patents

Double inhibiteur de kinase p38/src et leur utilisation comme agents thérapeutiques Download PDF

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WO2017087818A1
WO2017087818A1 PCT/US2016/062802 US2016062802W WO2017087818A1 WO 2017087818 A1 WO2017087818 A1 WO 2017087818A1 US 2016062802 W US2016062802 W US 2016062802W WO 2017087818 A1 WO2017087818 A1 WO 2017087818A1
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compound
cancer
alkyl
group
halo
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Matthew B. Soellner
Sameer PHADKE
Sofia D. Merajver
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The Regents Of The University Of Michigan
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present disclosure relates to dual Src/p38 kinase inhibitor compounds and their use as therapeutic agents.
  • TNBC triple negative breast cancer
  • TNBC Tumor et al., Breast cancer research and treatment 2013, 138(l):21-35.
  • TNBC is a large (and itself heterogeneous) subset of breast cancers for which there are no FDA-approved targeted therapies, and cytotoxic agents remain the mainstay of therapy (Bayraktar et al., supra).
  • C-Src a ubiquitously expressed kinase, participates in a number of important signal transduction pathways involved in cell adhesion, migration, invasion, angiogenesis, and survival (Playford et al., Oncogene 2004, 23(48):7928-7946; Summy et al., Cancer metastasis reviews 2003, 22(4):337-358; Yeatman TJ, Nature reviews Cancer 2004, 4(6):470-480; Finn RS, Annals of oncology 2008, 19(8): 1379- 1386).
  • C-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis.
  • c-Src Abnormal expression of c-Src has been detected in various tumors, and c-Src is typically highly overexpressed in TNBC (Aleshin A and Finn RS, Neoplasia 2010, 12(8):599-607; Mayer EL and Krop IE, Clinical cancer research 2010, 16(14):3526-3532; Tryfonopoulos et al., Annals of oncology 2011, 22(10):2234-2240; Sanchez-Bailon et al., Cellular signalling 2012, 24(6): 1276- 1286).
  • This overexpression of c-Src has been shown to play a role in oncogenic proliferation, migration, and invasion of TNBC cell lines (Tryfonopoulos et al., supra).
  • c-Src activity also regulates osteoclast function in healthy bone and enables bone metastases in metastatic TNBC (Finn, RS 2008, supra).
  • c-Src is a very attractive target as a possible treatment of TNBC.
  • Preclinical studies have validated c-Src as a therapeutic target in TNBC; however, existing c-Src inhibitors exhibited limited efficacy and high toxicity in the clinic (Finn et al., Clinical cancer research 2011, 17(21):6905-6913; Gucalp et al., Clinical breast cancer 2011, 11(5):306-311; Campone et al., Annals of ' 2012, 23(3):610-617), which has tempered the enthusiasm for c-Src inhibition as a strategy in TNBC.
  • ER-negative and mutant-p53 cell lines (which comprise a majority of TNBCs) have been observed to be more sensitive to small molecule inhibition of p38a than ER-positive and wt-p53 cell lines (Chen et al., Cancer research 2009, 69(23):8853-8861).
  • the activity of p38a activity has been demonstrated to promote oncogenesis via increased invasion, inflammation, and angiogenesis (Wagner et al., Nature reviews Cancer 2009, 9(8):537-549).
  • the exact contribution of ⁇ 38 ⁇ to MAPK signaling has not been fully elucidated, however, there is growing evidence that ⁇ 38 ⁇ activity correlates with increased proliferation of TNBC cells.
  • inhibiting p38a and ⁇ 38 ⁇ could lead to a potent anti-cancer effect.
  • the present disclosure is directed to dual Src/p38 kinase inhibitors and their use as therapeutic agents, e.g., to treat cancer.
  • the compounds of the disclosure potently inhibit both c- Src and p38 kinases.
  • the compounds of the disclosure block growth factor mediated signaling pathways and efficiently decrease motility and invasion of cancer cells such as TNBC cells and have a high therapeutic index in vivo.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
  • A is i_ 3 alkyl, NR 6 R 7 , or C 3-8
  • R 2 is , , or C5_ 6 heteroaryl
  • R 3 is H, OH, halo, Ci_ 3 alkyl, or OCi_ 2 alkyl
  • R 4 is H, halo, Ci_ 2 alkyl, or OCH 3
  • R 5 is H, Ci_ 3 alkyl, or OCi_ 3 alkyl
  • R 7 are each independently H, Ci_ 4 alkyl, C 3 _ 6 cycloalkyl, or C 3 _ 6 heterocycloalkyl;
  • R 8 is halo, C 1-3 alkylene-C 3 _ 8 heterocycloalkyl, or heteroaryl;
  • R 9 is H, Ci_ 4 alkyl, or halo;
  • R 10 is halo, Ci_ salkyl, OCi_ 4 alkyl, NR 6 R 7 , or Ci_ 3 alkylene-C 3 _ 8 heterocycloalkyl.
  • the compound is selected from the group consisting of
  • the present disclosure provides a composition comprising a compound described herein, for example, any of compounds CI to CI 3, a compound having the structure
  • the present disclosure provides a method of treating or preventing a neoplastic, hyperplastic, or hyperproliferative disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein.
  • the present disclosure provides a method of inhibiting cancer growth or metastasis comprising contacting a cancer cell with an effective amount of a compound disclosed herein.
  • the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein.
  • the compound is, for example, a compound of Formula (I), any one of compounds CI to C14, or a combination thereof.
  • the methods of the present disclosure may be used to treat a cancer selected from the group consisting of group consisting of breast cancer, bone cancer, bladder cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, multiple myeloma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, prostate cancer, sarcoma, skin cancer, testicular cancer, throat cancer, and thyroid cancer, for example, sarcoma, pancreatic cancer, colon cancer, lung cancer, prostate cancer, or breast cancer, including TNBC.
  • a cancer selected from the group consisting of group consisting of breast cancer, bone cancer, bladder cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, multiple myeloma, oral cancer, ovarian cancer, pancre
  • Figure 1 depicts the co-crystal structure of UM-164 bound to c-Src.
  • C-Src adopts the DFG-out inactive conformation (PDB: 4YBJ).
  • Figure 2A depicts c-Src autophosphorylation in MDA-MB 231 cells
  • Figure 2B depicts c-Src autophorphrylation in SUM 149 cells.
  • c-Src autophosphorylation was inhibited in a dose and time dependent manner by UM-164 treatment.
  • Figure 3A depicts Src activated signaling in SUM 149 cells treated with UM-164.
  • Figure 3B depicts Src activated signaling in SUM 149 cells treated with dasatinib.
  • Figure 3C depicts Src activated signaling in VARI-068 patient-derived triple negative breast cancer cells treated with UM-164.
  • Figure 4 depicts growth inhibition in MDA-MB-231 cells treated with dasatinib alone or in combination with a pan-p38 kinase, BIRB-796, or UM-164.
  • Figure 5A depicts cell cycle phase in MDA-MB 231 treated with UM- 1-64.
  • Figure 5B depicts cell cycle phase in SUM 149 cells treated with UM-164.
  • Figure 6A depicts the average track area covered by cells within a 24-hour time period for MDA-MB 231 (top) and SUM 149 (bottom) cells treated with 50 nM, 100 nM, or 250 nM UM-164 for 24 hours.
  • Figure 5B depicts the number of MDA-MB 231 (top) and SUM 149 (bottom) cells that migrated and invaded after 5 x 10 4 cells were plated and treated with 50 nM, 100 nM, or 250 nM UM-164 for 24 hours. Error bars represent standard deviation of triplicate experiments. *P ⁇ 0.001 using the Student's t-test to compare DMSO treated control and UM- 164-treated cells.
  • Figure 7 A depicts the tumor volume in MDA-MB 231 xenografted mice receiving vehicle, 10 mg/kg UM-164, or 20 mg/kg UM-164 every other day
  • Figure 7B depicts the tumor volume in SUM 149 xenografted mice receiving vehicle, 10 mg/kg UM-164, or 20 mg/kg UM- 164 every other day.
  • Statistical significance was determined at a threshold of 0.05 using Bonferroni multiple comparisons test.
  • the present disclosure provides dual Src/p38 kinase inhibitors that have antitumor, e.g., cytotoxic or cytostatic, activity against different types of hyperproliferative cells. Unlike other kinase inhibitors in clinical use, the compounds described herein are dual Src/p38 kinase inhibitors. The compounds inhibit signaling pathways involved in controlling tumor cell proliferation and survival and have anti-TNBC activity in vivo with limited toxicity.
  • c-Src inhibitors e.g., dasatinib, bosutinib, saracatinib
  • the compounds of the present disclosure inhibit c-Src in a specific inactive conformation (termed "DFG-out"), which results in improved efficacy against cancer cells.
  • DFG-out a specific inactive conformation
  • Preclinical target validation of c-Src has largely been performed using genetic techniques that ablate the entire c-Src gene, while pharmacological intervention with small molecules (such as dasatinib) inhibits only the kinase catalytic activity.
  • alkyl refers to straight chained and branched saturated hydrocarbon groups containing one to thirty carbon atoms, for example, one to twenty carbon atoms, or one to ten carbon atoms.
  • C n means the alkyl group has "n" carbon atoms.
  • C 4 alkyl refers to an alkyl group that has 4 carbon atoms.
  • C1-7 alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (i.e., 1 to 7 carbon atoms), as well as all subgroups (e.g., 1-6, 2-7, 1-5, 3-6, 1, 2, 3, 4, 5, 6, and 7 carbon atoms).
  • Nonlimiting examples of alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl (2-methylpropyl), i-butyl (1, 1-dimethylethyl), 3,3-dimethylpentyl, and 2-ethylhexyl.
  • an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.
  • alkylene refers to an alkyl group having a substituent.
  • alkylene- aryl refers to an alkyl group substituted with an aryl group.
  • C n means the alkylene group has "n" carbon atoms.
  • C 1-6 alkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for "alkyl” groups.
  • cycloalkyl refers to an aliphatic cyclic hydrocarbon group containing three to eight carbon atoms (e.g. , 3, 4, 5, 6, 7, or 8 carbon atoms).
  • C n means the cycloalkyl group has "n" carbon atoms.
  • C5 cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring.
  • C5-8 cycloalkyl refers to cycloalkyl groups having a number of carbon atoms encompassing the entire range (i.e., 5 to 8 carbon atoms), as well as all subgroups (e.g.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise indicated, a cycloalkyl group can be an unsubstituted cycloalkyl group or a substituted cycloalkyl group.
  • cycloalkyl groups described herein can be isolated, share a carbon atom with another cycloalkyl or heterocycloalkyl group, or fused to another cycloalkyl group, a heterocycloalkyl group, an aryl group and/or a heteroaryl group.
  • heterocycloalkyl or “heterocyclic” is defined similarly as cycloalkyl, except the ring contains one to three heteroatoms independently selected from oxygen, nitrogen, or sulfur.
  • heterocycloalkyl groups include piperdine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, and the like.
  • heterocycloalkyl groups described herein can be isolated, share a carbon atom with another cycloalkyl or heterocycloalkyl group, or fused to another heterocycloalkyl group, a cycloalkyl group, an aryl group and/or a heteroaryl group.
  • aryl refers to monocyclic or polycyclic (e.g. , fused bicyclic and fused tricyclic) carbocyclic aromatic ring systems.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, indenyl, anthracenyl, and fluorenyl.
  • an aryl group can be an unsubstituted aryl group or a substituted aryl group.
  • heteroaryl refers to monocyclic or polycyclic (e.g. , fused bicyclic and fused tricyclic) aromatic ring systems, wherein one to four-ring atoms are selected from oxygen, nitrogen, or sulfur, and the remaining ring atoms are carbon, said ring system being joined to the remainder of the molecule by any of the ring atoms.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.
  • a heteroaryl group can be an unsubstituted heteroaryl group or a substituted heteroaryl group.
  • halo refers to a fluoro, chloro, bromo, or iodo group
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen
  • chemotherapeutic agent refers to any compound that is toxic with respect to hyperproliferative cells (e.g., cancer cells) or inhibits the growth or proliferation of hyperproliferative cells and includes biologies, antibodies, small molecules, peptides and antisense oligonucleotides.
  • chemotherapeutic agents include, but are not limited to, an aromatase inhibitor, an anti-estrogen, an anti-androgen, a gonadorelin agonist, a
  • topoisomerase I inhibitor a topoisomerase II inhibitor, a microtubule active agent, an alkylating agent, a retinoid, a carotenoid, a tocopherol, a cyclooxygenase inhibitor, an MMP inhibitor, a mTOR inhibitor, an antimetabolite, a platin compound, a methionine aminopeptidase inhibitor, a bisphosphonate, an antiproliferative antibody, a heparanase inhibitor, an inhibitor of Ras oncogenic isoforms, a telomerase inhibitor, a proteasome inhibitor, a compound used in the treatment of hematologic malignancies, a Flt-3 inhibitor, an Hsp90 inhibitor, a kinesin spindle protein inhibitor, a MEK inhibitor, an antitumor antibiotic, a nitrosourea, a compound targeting/decreasing protein or lipid kinase activity, a compound targeting/decreasing protein or
  • antitumor agents include, but are not limited to, azacitidine, axathioprine, bevacizumab, bleomycin, capecitabine, carboplatin, chlorabucil, cisplatin, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fenretinide, fluorouracil, gemcitabine, herceptin, idarubicin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, tafluposide, teniposide, tioguanine, retinoic acid, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, receptor tyrosine kinase inhibitor
  • a therapeutically effective amount and “effective amount” depend on the condition of a subject and the specific compound(s) administered. The terms refer to an amount effective to achieve a desired biological, e.g., clinical effect. A therapeutically effective amount varies with the nature of the disease being treated, the length of time that activity is desired, and the age and the condition of the subject. In one aspect, a therapeutically effective amount of a compound or composition of the disclosure is an amount effective to inhibit growth of hyperproliferative cells, prevent cancer cell metastasis, and/or result in cancer cell death.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
  • A is R 1 is H, Ci_ 4 alkyl, OCi_ 4 alkyl, SCi_ 3 alkyl, NR 6 R 7 , or C 3-8
  • R is H, OH, halo, Ci_ 3 alkyl, or OCi_ 2 alkyl
  • R 4 is H, halo, Ci_ 2 alkyl, or OCH 3
  • R 5 is H, Ci_ 3 alkyl, or OCi_ 3 alkyl
  • R 6 and R 7 are each independently H, Ci_ 4 alkyl, 8
  • A is . In another aspect, A is .
  • R 1 is H, Ci_ 4 alkyl, OCi_ 4 alkyl, SCi_ 3 alkyl, NR 6 R 7 or C 3 _
  • R 1 is H.
  • R 1 is Ci_ 4 alkyl (e.g., methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, sec-butyl, or ieri-butyl).
  • R 1 can be CH 3 or CH 2 CH 3 .
  • R 1 is OCi_ 4 alkyl (e.g., OMe, OEt, OnPr, Oz ' Pr, OnBu, OsecBu, OtertBu).
  • R 1 can be OCH 3 or OCH 2 CH 3 .
  • R 1 is SCi_ 4 alkyl (e.g., SMe, SEt, SnPr, Sz ' Pr, SnBu, SsecBu, StertBu).
  • R 1 can be SCH 3 or SCH 2 CH 3 .
  • R 1 is NR 6 R 7 and R 6 and R 7 are each independently H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 isopropyl, tert-
  • R 1 is optionally HN ⁇
  • R 1 is C 3 _ 8 heterocycloalkyl, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, or oxathianyl.
  • R 1 is aziridinyl, piperazinyl, or morpholinyl, for example,
  • R 1 can be selected from the
  • R z is
  • R can be Ci_ 3 alkylene-C3_ 8 heterocycloalkyl, wherein the heterocycloalkyl is optionally piperazinyl or morpholinyl.
  • R can be CH 2 -pi -piperazinyl, CH 2 CH 2 CH 3 - piperazinyl, or CHCH 3 CH 3 -piperazinyl, such as can be heteroaryl (e.g., pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, furanyl, quinolinyl, isoquinolinyl, benzoxazolyl, yl, or benzothiazolyl).
  • R can be imidazolyl or
  • R 8 is can
  • R 9 is H.
  • R 9 is Ci ⁇ alkyl (e.g., CH 3 or tBu).
  • R 9 is halo (e.g., F, CI, or Br).
  • R 10 is halo (e.g., F or CI).
  • R 10 is Ci_ 4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl).
  • R 10 is OCi_ 2 alkyl (e.g., OMe or OEt).
  • R 10 is NR 6 R 7 . In some of these cases, R 6 and R 7 are each independently H or Ci_ 4 alkyl (e.g., CH 3 or
  • R 10 is F, .
  • R2 can be selected from the group consisting of .
  • R 2 is C5_ 6 heteroaryl, wherein heteroaryl optionally is pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, furanyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.
  • heteroaryl optionally is pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadia
  • R 2 is
  • R 3 is H, OH, halo, Ci_ 3 alkyl, or OCi_ 2 alkyl (e.g., OCH 3 or OCH 2 CH 3 ).
  • R 3 is H. In another aspect, R 3 is OH. In some aspects, R 3 is halo (e.g., F or CI).
  • R 3 is Ci_ 3 alkyl (e.g., methyl, ethyl, n-propyl, or isopropyl).
  • R 3 can be CH 3 or CH 2 CH 3 .
  • R 3 is OCi_ 2 alkyl (e.g., OMe or OEt).
  • R 3 is
  • R 4 is H, halo, Ci_ 2 alkyl, or OCH 3.
  • R 4 is H.
  • R 4 is halo (e.g., F or Br).
  • R 4 is Ci_ 2 alkyl (e.g., CH 3 or CH 2 CH 3 ).
  • R 4 is OCH 3 .
  • R 5 is H, Ci_ 3 alkyl, or OCi_ 3 alkyl.
  • R 5 is H.
  • R 5 is Ci_ 3 alkyl (e.g., methyl, ethyl, n-propyl, or isopropyl).
  • R 5 can be CH 3 or CH 2 CH 3 .
  • R 5 is OCH 3 .
  • R 1 is selected from the group consisting of CH 3 ,
  • R is selected from the group consisting of C3 ⁇ 4, CH 2 CH 3 , OCH 3 , and OH; R is
  • A is R 1 is selected from the group consisting of CH 3 ,
  • R 5 is CH 3 .
  • the compound of Formula (I) has a structure selected from the group consisting of:
  • composition comprising a compound described herein, e.g., one or more of compounds CI to C13 or a compound having the structure
  • the composition is for use in the treatment of a neoplastic, hyperplastic, or hyperproliferative disease, such as cancer.
  • Pharmaceutically acceptable carriers include, but are not limited to, water, saline, phosphate buffered saline, and buffers.
  • the carrier is sterile.
  • Other excipients, including buffering agents, dispersing agents, and preservatives, are known in the art and may be included in the composition. Further examples of components that may be employed in compositions are presented in Remington's Pharmaceutical Sciences, 16 th Ed. (1980) and 20 th Ed. (2000), Mack Publishing Company, Easton, Pa.
  • a composition may be in any suitable dosage form including, but not limited to, tablets, capsules, implants, depots, liquids, patches, lozenges, creams, ointments, lotions, aerosols, and eye drops.
  • a method of treating a neoplastic, hyperplastic, or hyperproliferative disorder in a subject in need thereof comprises administering a therapeutically effective amount of a compound or composition described herein to the subject.
  • a method of treating cancer in a subject in need thereof also is provided comprising administering a therapeutically effective amount of a compound or composition described herein to the subject.
  • a method of inhibiting cancer growth or metastasis comprising contacting a cancer cell with an effective amount of the compound or composition described herein is provided.
  • a method of the present disclosure comprises administering any one of compounds CI to C 14 or a combination thereof.
  • a compound or composition described herein may be administered in an amount effective to inhibit the kinase activity of c-Src and/or p38. The ability of the compounds and
  • compositions of the present disclosure to inhibit kinase activity necessary for cancer growth and metastasis provides therapeutic efficacy in treating a wide range of cancer types.
  • the cancer is selected from the group consisting of breast cancer, bone cancer, bladder cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, multiple myeloma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, prostate cancer, sarcoma, skin cancer, testicular cancer, throat cancer, and thyroid cancer.
  • the cancer is sarcoma, pancreatic cancer, colon cancer, lung cancer, prostate cancer, or breast cancer, optionally triple negative breast cancer.
  • treating a cancer does not require complete eradication of the cancer. Any beneficial physiologic response is contemplated, such as tumor stasis, tumor shrinkage, tumor cell death, reduction or halting or delay of metastasis, reduction in cancer cell markers, alleviation of symptoms and the like.
  • a method of inhibiting cancer growth or metastasis comprises contacting a cancer cell with an effective amount of a compound or composition described herein.
  • a therapeutically effective amount of a compound or composition described herein, typically formulated in accordance with pharmaceutical practice is administered to a subject in need thereof.
  • administration regimen for a given subject will depend, in part, upon the compound or composition, the amount administered, the route of administration, and the cause and extent of any side effects.
  • the amount administered to a subject e.g., a mammal, such as a human
  • Dosage typically depends upon the route, timing, and frequency of administration.
  • the methods of the present disclosure comprise administering, e.g., from about 0.1 mg/kg to about 150 mg/kg or more of a compound of the disclosure based on the weight of the tumor or body weight of the subject, depending on the factors mentioned above.
  • the dosage ranges from about 0.1 mg/kg to about 0.5 mg/kg, about 5 mg/kg to about 75 mg/kg, about 10 mg/kg to about 50 mg/kg, about 80 mg/kg to about 120 mg/kg, about 15 mg/kg to about 30 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 10 mg/kg to about 25 mg/kg.
  • the dosage is administered as needed, for example, continuously, one to three times daily, every other day, twice a week, weekly, every two weeks, monthly, or less frequently.
  • the treatment period will depend on the particular condition and may last one day to several days, weeks, months, or years.
  • the above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure.
  • Suitable methods of administering a physiologically acceptable composition are well known in the art. Although more than one route can be used to administer a compound, a particular route can provide a more immediate and more effective reaction than another route.
  • a composition comprising one or more compounds described herein is introduced into tumor sites, applied or instilled into body cavities, absorbed through the skin or mucous membranes, inhaled, ingested and/or introduced into circulation.
  • the compound or composition is administered orally.
  • the compound or composition is injected intravenously and/or intraperitoneally.
  • the compound or composition is administered locally by directly contacting cancer cells with the compound or composition.
  • compositions through injection or infusion by intravenous, intratumoral, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal,
  • the composition is administered via implantation of a matrix, membrane, sponge, or another appropriate material onto which the compound has been absorbed or encapsulated.
  • the device is, in one aspect, implanted into any suitable tissue or organ, and delivery of the desired compound is, for example, via diffusion, timed-release bolus, or continuous administration.
  • the compound may be attached to a targeting moiety specific for a tumor cell, such as an antigen binding protein including, but not limited to, antibodies, antibody fragments, antibody derivatives, antibody analogs, and fusion proteins, that bind a specific tumor cell antigen.
  • a targeting moiety specific for a tumor cell such as an antigen binding protein including, but not limited to, antibodies, antibody fragments, antibody derivatives, antibody analogs, and fusion proteins, that bind a specific tumor cell antigen.
  • the compounds of the present disclosure may be used in combination with other therapeutic agents.
  • antitumor therapies that can be used in combination with the compounds and compositions include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, biologic response modifiers (e.g., interferon, interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy), agents to attenuate any adverse effect (e.g., antiemetics), gene therapy, viruses, and any other chemotherapeutic agent.
  • TNF tumor necrosis factor
  • cryotherapy agents to attenuate any adverse effect
  • gene therapy e.g., viruses, and any other chemotherapeutic agent.
  • Tumor growth can be analyzed to determine the therapeutic activity of the compounds of the present disclosure.
  • Tumor mass, volume, and/or length can be assessed using methods known in the art such as calipers, ultrasound imaging, computed tomography (CT) imaging, magnetic resonance imaging (MRI), optical imaging (e.g., bioluminescence and/or fluorescence imaging), digital subtraction angiography (DSA), positron emission tomography (PET) imaging and/or other imaging analysis.
  • Tumor cell proliferation can also be analyzed using cellular assays that measure, e.g., DNA synthesis, metabolic activity, antigens associated with cell proliferation, and/or ATP.
  • the method of the present disclosure reduces the size of a tumor at least about 5% (e.g., at least about 10%, at least about 15%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%).
  • the method of the present disclosure maintains the tumor size, i.e., prevents further growth of the tumor, for a period of at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • MCF-IOA, MDA-MB 231, Hs578t, HCC1937, and MDA-MB 468 cells were obtained from American Type Culture Collection (Manassas, VA, USA) and cultured in the recommended media. Each cell line was used within 6 months of initial purchase. HME cells were obtained from Lonza and used within 6 months of purchase.
  • the SUM149 cell line was provided by Dr. Stephen P. Ethier and authenticated via ATCC (STR # 13868). SUM149 cells were cultured in Ham's F-12 media (JRH Biosciences, Lenexa, KS) supplemented with 5% fetal bovine serum containing insulin and hydrocortisone (Sigma Chemical Co., St.
  • VARI-068 cell line was derived from a TNBC patient-derived xenograft (PDX).
  • PDX TNBC patient-derived xenograft
  • the patient tumor was obtained from the Van Andel Research Institute (Grand Rapids, MI) and was propagated as a PDX.
  • the cell line from the PDX was cultured in RPMI-1640 medium supplemented with 10% FBS.
  • Dasatinib (pharmacological grade) was purchased from LC Laboratories (Boston, MA).
  • Synthesis ofS6 Compound S5 (1.4 g, 4.7 mmol) and sodium hydroxide (1.5 g, 37.5 mmol) were added to an oven-dried round bottom flask. Methanol (11 mL) and water (4 mL) were then added. The reaction was stirred at room temperature for 48 hours. Methanol was then removed under reduced pressure. The crude reaction mixture was then suspended in 1 N HCI and filtered. After drying, S6 (0.95 g, 75 % yield) was obtained as a white solid.
  • the cells were plated at about 1.0 x 10 4 cells per well (100 ⁇ ) in triplicate for each compound concentration.
  • Bead motility assay Motility of cancer cells was measured using a blue fluorescent bead motility assay (Cellomics, Cell Motility Kit, Thermo Scientific, Rockford, IL). Briefly, both MDA-MB 231 and SUM 149 cells were grown to 70-80% confluency. The cells were trypsinized and seeded at a density of 500 to 600 cells/well onto a lawn of blue microscopic fluorescent beads plated on a collagen-I coated 96-well plate. Cells were treated with both vehicle (DMSO) and UM-164 at concentrations 50 nM, 100 nM, and 250 nM prior to seeding and allowed to migrate overnight at 37 °C. As cells moved across the lawn, they
  • Cell invasion assays were determined as described from the cell invasion assay kit (Chemicon International, Temecula, CA). Briefly, cells were trypsinized, washed in PBS, and resuspended in serum- free media and plated at a concentration of 25,000 to 50,000 cells/well in the upper chamber of a 24-transwell plate. The lower chamber of the transwell were filled with Dulbecco's modified Eagles medium supplemented with 10% fetal bovine serum. Cells were allowed to migrate for 24 hours.
  • Non-migratory cells on the upper membrane surface were removed with a cotton swab, and the migratory cells attached to the bottom surface of the membrane were fixed with 100% ethanol followed by staining with 0.1% crystal violet for 40 minutes.
  • Five fields from the well were selecting using 20x fields from all four corners and one center field for quantification. Each determination represents the average of three independent experiments and error bars represent SD.
  • MTT assay was carried out to determine the inhibitory concentration (IC), which inhibits cell viability at 20, 40, and 50 %.
  • IC inhibitory concentration
  • each cell type was grown in the recommended medium.
  • Cell proliferation studies were done by plating cells (5 to 8 x 10 4 cells per well) in 96-well multi-well dishes (Corning, Inc., NY). After a 24-hour attachment period, the medium was aspirated and replaced with serum-free medium containing increasing concentration of drug (0.01 nmol/L to 10 ⁇ /L) (or vehicle control) for 72 hours.
  • MTT 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide
  • PVDF polyvinylidene fluoride
  • Polyclonal antibodies to fibronectin were obtained from Roche Applied Science. Propidium iodide was obtained from Boehringer Mannheim Corporation (Indianapolis, IN).
  • Xenograft study NCr/nude mice 6 weeks of age were obtained from Taconic Biosciences (Germantown, NY) and housed in pathogen-free conditions. Mice were anesthetized by injecting ketamine/xylazine combination at a concentration of 100 mpk/10 mpk. Ten thousand MDA-MB 231 cells were mixed with matrigel (BD Biosciences, San Jose, CA) in 1: 1 ratio by volume and injected into both left and right fourth mammary fat gland. Mice were randomized to treatment groups when the tumors were palpable. UM-164 was dissolved in a mixture of DMSO/propylene glycol (1:9) (Sigma- Aldrich).
  • the volume of administration was 0.05 ml/mouse.
  • the control group received 10% DMSO, and the treatment groups received 10 mg/kg or 20 mg/kg of drug.
  • Mice were treated every alternate day intraperitoneally for up to 52 consecutive days.
  • the tumors were monitored twice a week, and the mice body weight was measured weekly.
  • the mean tumor volume and tumor weight for each treatment was compared to the vehicle treated group for statistical significance using two-tailed student' s t-test.
  • UM-164 inhibited c-Src in an inactive conformation.
  • UM-164 (C14) binds c-Src and forces a DFG-out inactive conformation. Crystallographic studies confirmed that UM- 164 bound c-Src in the DFG-out, inactive conformation (PDB code: 4YBJ) ( Figure 1).
  • UM-164 Kd 2.7 nM
  • UM-164 has potent anti-TNBC activity in vitro.
  • Triple-negative breast cancers are highly diverse and heterogeneous lesions.
  • a panel of cell lines was selected, and the expression of activated c-Src was determined by probing the total cell lysate with an antibody that specifically recognizes the activated form of c-Src (pY419).
  • VARI- 062 patient-derived TNBC cell line
  • HMEC primary human mammary epithelial cells
  • MCF-IOA immortalized nonmalignant, normal-like cell line
  • HMEC primary human cells
  • SUM 149 cells were treated with the indicated concentrations of UM-164 or dasatinib for 24 hours and the phospho- and total protein levels of EGFR, p38MAPK, AKT, and p44/42MAPK were examined by western blot analysis.
  • UM-164 was a potent inhibitor of p38oc and ⁇ 38 ⁇ , whereas no FDA-approved c-Src inhibitor (e.g., dasatinib, bosutinib, saracatinib) has been identified as potently inhibiting both p38oc and ⁇ 38 ⁇ . Consistent with UM-164 being a potent p38 inhibitor, p38MAPK phosphorylation was totally absent in SUM 149 cells treated with 50 nM of UM-164.
  • FDA-approved c-Src inhibitor e.g., dasatinib, bosutinib, saracatinib
  • UM-164 inhibited TNBC cell motility and invasion.
  • C-Src is an important mediator of cell migration signaling pathways through its role in controlling the dynamics of focal adhesions.
  • the MDA-231 and SUM149 cell lines were pretreated with UM-164 and 24 hours after pretreatment, the viable cells were plated for invasion and similar results were obtained, confirming that the observed effect was due to inhibition in the invasive properties of the cells rather than to cell death.
  • Enhanced migratory activity is linked to increased cross activation of c-Src and FAK activity.
  • FAK phosphorylation was inhibited by UM-164 in SUM 149 cells.
  • paxillin which serves as an adaptor protein in cell adhesion and is a substrate for the FAK-SRC complex was likewise inhibited in SUM- 149 cells.
  • mice were injected intraperitoneally with either drug or vehicle every other day.
  • the selected doses which represented 7 and 14% of the MTD for 10 and 20 mg/kg UM-164, respectively
  • tumor growth was significantly (p ⁇ 0.024, 0.004) inhibited in both the 10 mg/kg and 20 mg/kg dose groups compared to the vehicle treated group ( Figures 7A and 7B).
  • total protein from tumor lysates from both control and treated groups were analyzed for the expression of P-p38MAPk, P-EGFR, and P-Src.
  • the compounds of the disclosure may also be delivered via other modes of administration, such as oral or intravenous delivery.
  • Pharmacokinetic studies of compound C01 administered intravenously at a dosage of 15 mg/kg found the compound to have an AUC(0-24) of 5807.8 hr*ng/mL, an AUC(O-infinity) of 5834.6 hr*ng/mL, a half-life (ti /2 ) of 5.9 hr, a volume of distribution during terminal phase (Vz) of 22021.9 mL/kg and a clearance (CL) of 2570.8 mL/hr/kg.
  • Novel c-Src inhibitors that specifically binds the DFG-out inactive conformation of target kinases were synthesized. Binding the inactive kinase conformation led to a phenotype similar to gene knockdown of c-Src.
  • the exemplary compound UM- 164 (C14) was highly active against diverse TNBC cell lines in vitro and active in 3D cell culture.
  • Kinome profiling of UM-164 identified p38a and ⁇ 38 ⁇ as being potently inhibited by UM-164 and dose-dependent inhibition of p38MAP kinases was observed both in vitro and in vivo.
  • UM-164 suppressed cell migration and invasion in MDA-MB 231 and SUM149 cells.
  • the significant decrease in tumor growth in vivo correlated with a decrease in p-P38MAPK, p-EGFR and p-Src.
  • UM-164 was active in vivo with excellent anti-TNBC activity and limited toxicity.
  • UM-164 binds the inactive kinase conformation of c-Src.
  • Kinome-wide profiling of UM-164 identified Src family and p38MAP kinases were potently inhibited by UM-164.
  • Treatment with UM-164 resulted in a significant decrease in vivo of tumor growth for MDA-MB 231 and SUM149 xenografts.
  • Dual c-Src/p38 inhibition was significantly more efficacious compared to mono-inhibition of c-Src or p38.
  • the compounds of the present disclosure are kinase inhibitors that potently inhibit c-Src, p38a, and ⁇ 38 ⁇ , without potently inhibiting the majority of the rest of the kinome.

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Abstract

L'invention concerne des composés doubles inhibiteurs de kinase P38/Src et des compositions les comprenant. L'invention concerne également des méthodes d'utilisation des composés dans le traitement de maladies hyperprolifératives comme le cancer.
PCT/US2016/062802 2015-11-19 2016-11-18 Double inhibiteur de kinase p38/src et leur utilisation comme agents thérapeutiques WO2017087818A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114224892A (zh) * 2021-11-23 2022-03-25 中国科学院深圳理工大学(筹) Tipe2抑制剂及其应用、筛选方法及筛选装置

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004150A1 (en) * 2003-03-25 2005-01-06 Guy Brenchley Thiazoles useful as inhibitors of protein kinases
US20060160857A1 (en) * 2005-01-14 2006-07-20 Bernd Buettelmann Thiazole-4-carboxyamide derivatives
US20090181963A1 (en) * 2008-01-15 2009-07-16 Wyeth 3H-[1,2,3]TRIAZOLO[4,5-D]PYRIMIDINE COMPOUNDS, THEIR USE AS mTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
WO2015090259A1 (fr) * 2013-12-19 2015-06-25 Zentiva, K.S. Procédé de préparation de forme n-6 polymorphe anhydre de dasatinib

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004150A1 (en) * 2003-03-25 2005-01-06 Guy Brenchley Thiazoles useful as inhibitors of protein kinases
US20060160857A1 (en) * 2005-01-14 2006-07-20 Bernd Buettelmann Thiazole-4-carboxyamide derivatives
US20090181963A1 (en) * 2008-01-15 2009-07-16 Wyeth 3H-[1,2,3]TRIAZOLO[4,5-D]PYRIMIDINE COMPOUNDS, THEIR USE AS mTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
WO2015090259A1 (fr) * 2013-12-19 2015-06-25 Zentiva, K.S. Procédé de préparation de forme n-6 polymorphe anhydre de dasatinib

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114224892A (zh) * 2021-11-23 2022-03-25 中国科学院深圳理工大学(筹) Tipe2抑制剂及其应用、筛选方法及筛选装置
WO2023092740A1 (fr) * 2021-11-23 2023-06-01 中国科学院深圳理工大学(筹) Inhibiteur de tipe2 et son utilisation, et procédé de criblage et dispositif associé

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