WO2019183385A1 - Inhibition de mapk/erk pour le traitement du cancer de l'ovaire et d'autres cancers - Google Patents

Inhibition de mapk/erk pour le traitement du cancer de l'ovaire et d'autres cancers Download PDF

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Publication number
WO2019183385A1
WO2019183385A1 PCT/US2019/023420 US2019023420W WO2019183385A1 WO 2019183385 A1 WO2019183385 A1 WO 2019183385A1 US 2019023420 W US2019023420 W US 2019023420W WO 2019183385 A1 WO2019183385 A1 WO 2019183385A1
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cancer
inhibitor
mek
urml
compound
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PCT/US2019/023420
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English (en)
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Rakesh K. Singh
Richard G. Moore
Kyu Kwang Kim
Rachael Turner
Negar KHAZAN
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University Of Rochester
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • 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

Definitions

  • This invention relates to cancer therapy.
  • Ovarian cancer is the 9th most common cancer afflicting American women, with an estimated 22,280 new cases in 2016. It is most often diagnosed at advanced stages, making it the 5th leading cause of cancer deaths among women, with approximately 14,240 deaths per year.
  • Clear cell ovarian cancer (CCOC) is a high-grade subtype that comprises about 10% of all ovarian cancers. CCOC tends to be more chemotherapy resistant and as such, portends a worse prognosis. Despite poor response rates, the standard adjuvant first-line treatment for CCOC is chemotherapy. Due to the lack of current effective treatments, there is an urgent need for novel CCOC therapies.
  • the invention provides a solution to long standing problems in treating cancers such as chemotherapy resistant cancers.
  • compositions and methods of treating a cancer in a subject comprising administering to the subject an inhibitor of MAPK/ERK Kinase (MEK), e.g., an ovarian cancer such as clear cell ovarian cancer or a pancreatic cancer or melanoma.
  • MEK MAPK/ERK Kinase
  • a composition comprising an inhibitor of MAPK/ERK Kinase (MEK) for use in treating cancer or other proliferative disorders is also within the invention.
  • the invention features a composition comprising a selective inhibitor of MAPK/ERK Kinase (MEK), wherein the inhibitor reduces activity of MEK1 and/or MEK2.
  • MEK MAPK/ERK Kinase
  • the composition comprises a compound with the following structure:
  • the inhibitor of MEK does not substantially reduce activity of MEK3 and/or
  • the invention includes a compound of Formula I:
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • p is 0 or 1;
  • X is H or Ci-C 6 alkyl
  • Y is F, Cl, Br, I, N0 2 , CH , or CF 3 ;
  • R in each instance is independently F, Cl, Br, I, N0 2 , CFf, or CF 3 .
  • X is H or CH 3 .
  • R in each instance comprises F, Cl, Br, or I.
  • the invention also encompasses a pharmaceutical composition comprising at least one of the MEK-inhibiting compounds described herein, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises an additional therapeutic agent, e.g., an anticancer agent.
  • an anticancer agent include one or more platinum analogues.
  • An exemplary method of treating a cancer in a subject in need thereof is carried out by administering to the subject a therapeutically effective amount of at least one of the MEK- inhibiting compounds, or a pharmaceutically acceptable salt thereof.
  • the subject is characterized as, e.g., diagnosed as, comprising a cancer such as ovarian cancer, pancreatic cancer, melanoma, medulloblastoma, or neuroblastoma.
  • the cancer is clear cell ovarian cancer.
  • the compound is administered orally.
  • At least one of the MEK-inhibiting compounds described herein, e.g., URML-3881, is administered at a dosage of about 0.001 mg/kg to about 1000 mg/kg, about 0.01 mg/kg to about 1000 mg/kg, about 0.1 mg/kg to about 1000 mg/kg, about 1 mg/kg to about 1000 mg/kg, about 1 mg/kg to about 500 mg/kg, about 1 mg/kg to about 300 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 50 mg/kg, about 10 mg/kg to about 300 mg/kg, about 10 mg/kg to about 100 mg/kg, about 10 mg/kg to about 50 mg/kg, or other dosages determined suitable, for a human subject.
  • URML-3881 is administered at a dosage of about 0.001 mg/kg to about 1000 mg/kg, about 0.01 mg/kg to about 1000 mg/kg, about 0.1 mg/kg to about 1000 mg/kg, about 1 mg/kg to about 1000 mg/kg, about 1
  • Compounds described herein can be administered as needed for treatment, e.g., daily, weekly, monthly, bi-monthly, or as indicated by the condition of the subject.
  • An additional anticancer agent is optionally administered.
  • the additional anticancer agent is a platinum analogue.
  • the method may encompass treatment comprising URML-3881 and a platinum analogue such as cisplatin.
  • the method of treating a cancer in a subject comprises administering to a subject, e.g., a cancer patient, an inhibitor of MAPK/ERK Kinase (MEK), wherein the inhibitor reduces activity of MEK1 and/or MEK2.
  • a subject e.g., a cancer patient
  • an inhibitor of MAPK/ERK Kinase MEK
  • the inhibitor does not substantially reduce activity of MEK3 and/or MEK5.
  • the inhibitor does not comprise trametinib or cobinetinib.
  • An exemplary subject to be treated is one comprising a cancer.
  • the cancer comprises ovarian cancer such as an epithelial ovarian cancer.
  • the subject to be treated may be characterized as suffering from or diagnosed as comprising a clear cell ovarian cancer (CCOC).
  • CCOC clear cell ovarian cancer
  • the subject to be treated is characterized as suffering from or diagnosed as comprising ovarian cancer, pancreatic cancer, melanoma, medulloblastoma, or neuroblastoma.
  • the inhibitor of MAPK/ERK Kinase is selective, e.g., is specific for MEK1 and/or MEK2. In preferred embodiments, the inhibitor does not bind to MEK3 or MEK5.
  • the method further comprises administering to the subject platinum chemotherapy or
  • PI3K/mTOR inhibitory therapy PI3K/mTOR inhibitory therapy.
  • Abbreviations used herein include the following terms: MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; HGF, hepatocyte growth factor; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; KSR1, kinase suppressor of Ras 1.
  • FIG. l is a series of photomicrographs showing that MAPK pathway expression in human CCOC is heterogeneously elevated. Representative pictures for p-ERK (green) staining from patient samples of either CCOC, serous ovarian cancer or adjacent normal ovarian tissue are shown. Images are overlaid to also show cell nuclei in blue (DAPI).
  • DAPI cell nuclei in blue
  • FIG 2A is a depiction of the chemical structure of URML-3881, a MEK inhibitor, showing its chemical structure, chemical formula, and exact mass (calculated exact mass obtained by summing the masses of the individual isotopes of the molecule).
  • FIG. 2B is a bar graph showing percent kinase activity in the presence of URML-3881 (30 nM), compared to kinase activity at baseline.
  • FIG. 2C is a photograph showing the results of a western blot assay.
  • CCOC cell lines OMANA and OVTOKO
  • ETRML-3881 for 24 hrs.
  • Cell lysates were then obtained and p-ERK, ERK, p-MEK and MEK protein expression was determined by western blot using corresponding antibodies.
  • FIG. 2D is a diagram of the MAPK pathway at baseline, with MEK inhibition, when over-activated (as in CCOC), and when over-activated with MEK and RAF inhibition.
  • FIG. 3 A is a bar graph showing viability of cancer cells treated with URML-3881. Six CCOC cell lines were cultured in the presence of 20 mM URML-3881 for 24 hrs and viability was determined as percentage of control tumor cell growth (DMSO as control).
  • FIG. 3B is a series of line graphs showing cancer cell viability and dose response to URML-3881.
  • the same six cells lines shown in FIG. 3 A were cultured in serial dilutions of URML-3881 for 24 hrs and viability was determined as percentage of control tumor cell growth.
  • FIG. 3C is a photograph showing the results of a western blot assay.
  • Six clear cell ovarian cancer cell lines were lysed and assessed for r-REA-15 and PEA- 15 protein expression (per 10 pg of protein from cell lysate) by western blot.
  • FIG. 3D is a bar graph showing cancer cell proliferation in response to treatment with EIRML-3881.
  • OVMANA cells were cultured in the presence of serial dilutions of EIRML-3881 for 48 hrs and proliferation was assessed by BrdET incorporation. Proliferation rate is expressed as a percentage with DMSO (control) treated cells used as a reference.
  • FIG. 3E is a bar graph showing cancer cell apoptosis in in response to treatment with EIRML-3881.
  • OVMANA cells were cultured with ETRML-3881 (5 and 20 pM) for 24 hrs and apoptotic status of cells was assessed by flow cytometry.
  • 7-AAD uptake dead cells.
  • AnnexinV staining actively dying or dead cells.
  • FIG 4A is a photograph of the results of a western blot assay.
  • An art-recognized humanized mouse model for human cancer in which human tumor tissue is engrafted into immunodeficient NOD SCID gamma (NSG mice) were used.
  • An in vivo mouse model of human cancer in which lxlO 6 OVMANA cells were injected subcutaneously into the flank of NSG mice and allowed 8 weeks to establish into tumors was used to generate the data described herein.
  • NSG mice with established OVMANA xenografts were treated with one dose of oral ETRML- 3881 at 30 mg/kg or control and sacrificed 2.5 hrs later. Protein was isolated from the tumors and p-ERK and ERK were analyzed by western blot. NSG mice with established OVMANA xenografts were treated with one dose of oral EIRML-3881 at 30 mg/kg or control and sacrificed 2.5 hrs later. Protein was isolated from the tumors and p-ERK and ERK were analyzed by western blot.
  • FIG. 4B is a line graph showing animal weight in response to treatment with EIRML- 3881.
  • NSG mice with established OVMANA xenografts were treated daily with ETRML-3881 (10 mg/kg or 30 mg/kg) or control by oral gavage for 21 days, animal weight was measured weekly throughout treatment
  • FIG. 4C is a line graph showing tumor volume in animals in response to treatment with EIRML-3881. Tumor volume was measured weekly throughout treatment and for 5 weeks afterwards.
  • FIGS. 4A-C show that EIRML-3881 inhibits the MAPK pathway in CCOC in vivo , but a higher dose and/or increased frequency of dosing may be necessary to achieve desirable in vivo activity as a single agent.
  • FIG. 5A is a photograph of the results of a western blot assay.
  • Alkylating agents are a class of chemotherapeutics that are known to induce ovarian cancer cell death by the inhibition of proliferation and the induction of apoptosis.
  • Six CCOC cells lines were treated with an exemplary platinum-based chemotherapeutic agent with such activity, cisplatin.
  • Cisplatin was tested at 10 or 30 pM for 24 hrs, cell lysates were then collected and assessed for p-ERK/ERK expression.
  • FIG. 5B is a photograph of the results of a western blot assay.
  • OVMANA cells were pretreated with ETRML-3881 or control (DMSO) one day before exposure to cisplatin chemotherapy and MAPK pathway and PI3k/AKT pathway activity was determined by western blot.
  • FIG. 5C is a bar graph showing cancer cell viability in response to URML-3881 treatment.
  • OVMANA cells were pretreated with URML-3881 (2.5 or 10 mM) or control (DMSO) one day before exposure to chemotherapy (cisplatin 10 or 30 pM) for 24 hrs. Cell viability was then determined and reported as percentage compared to control.
  • FIG. 5D is a depiction of a model treatment scheme.
  • Model animals, NSG mice, with established OVMANA xenografts were subjected to the model treatment scheme. Starting 8 weeks after tumor implantation, the animals were treated daily with oral URML-3881 (30mg/kg) or control (PBS) by oral gavage for 21 days starting on D-l and treated with 3 doses of weekly intraperitoneal cisplatin (4mg/kg) or control (PBS) starting on DO (arrows).
  • FIGS. 5A-F show that treatment with EIRML-3881 abrogates cisplatin-induced prosurvival MAPK signaling in CCOC, resulting in durable and dramatic tumor regression in vivo.
  • FIG. 6A is a diagram showing a method of synthesis for EIRML-3881.
  • FIG. 6B is a photograph of the results of a western blot assay.
  • MEK inhibitors URML- 3881 and AS703026 decrease p-ERK expression but result in enhanced p-MEK.
  • OVMANA cells were cultured in the presence of URML-3881, AS703026, sorafenib or R05126766 for 24 hours at the indicated doses. Cell lysates were then obtained and p-ERK, ERK, p-MEK and MEK protein expression was determined by western blot.
  • FIG. 7A is a bar graph showing the results of a cell viability assay. This figure shows results using OVMANA, an ovarian cancer.
  • FIG. 7B is a bar graph showing the results of a cell viability assay. This figure shows results using A2058, a melanoma cancer.
  • FIG. 7C is a bar graph showing the results of a cell viability assay. This figure shows results using BXPC3, a pancreatic cancer.
  • FIG. 7D is a bar graph showing the results of a cell viability assay. This figure shows results using D283, a medulloblastoma cancer.
  • FIG. 8 is a bar graph showing the results of an assay using IMR32 cells (neuroblastoma cancer cell type).
  • FIG. 9 is a bar graph showing the results of an assay using SMSKCNR cells
  • FIG. 10 is a bar graph showing the results of an assay using ES-2 cells (ovarian cancer cell type).
  • FIG. 11 is a bar graph showing the results of an assay using A2780 cells (ovarian cancer cell type).
  • the invention described herein provides compounds, compositions and methods of treatment for ovarian and other cancers.
  • the mitogen-activated protein kinase (MAPK) pathway also known as the
  • Ras/Raf/MEK/ERK pathway is vital to the survival of tumor cells. It is an intracellular signaling cascade by which activation of receptor tyrosine kinases at the cell surface can be transmitted to gene expression pathways.
  • MAPK signaling is known to play a role in the survival, proliferation, migration and angiogenesis of tumor cells.
  • VEGF vascular endothelial growth factor
  • EGFR epidermal growth factor receptor
  • MET hepatocyte growth factor receptor
  • prosurvival signaling through this pathway is known to confer a chemotherapy resistant phenotype to tumor cells.
  • Potent MEK inhibitors e.g., a compound of Formula I, such as EIRML-3881
  • the compounds target i.e., are selective for, MEK1 and 2 isoforms over other MEK isoforms and/or other kinases.
  • Chemotherapeutic agent such as an alkylating agent or alkylating-like agent that induces cancer cell death by apoptosis.
  • Chemotherapeutics include platinum-based anti -neoplastic agents or drugs.
  • platinum-based antineoplastic drugs are chemotherapeutic agents used to treat cancer. These chemotherapeutic drugs are complexes comprising platinum. Exemplary platinum-based drugs such as cisplatin, oxaliplatin, and carboplatin are shown below
  • Anti-neoplastic drugs (chemotherapeutic drugs) useful in the invention include paclitaxel, doxorubicine, topotecan, EGFR inhibitors, PI-3K and AKT inhibitors as well as rapamycin and its analogs for treatment regimens exemplify the preferred compounds for combination therapy for treatment of malignancies with URML-3881.
  • treating and “treatment” as used herein refer to the administration of an agent or formulation to a clinically symptomatic individual afflicted with an adverse condition, disorder, or disease, so as to effect a reduction in severity and/or frequency of symptoms, eliminate the symptoms and/or their underlying cause, and/or facilitate improvement or remediation of damage.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of therapeutic compound, such as a small molecule, an oligonucleotide, small molecule, antibody, or any other anticancer therapy, administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • “Purified chemical compound” (such as a small molecule chemical compound) as used herein means the compound is sufficiently free of chemical contaminants resulting from its isolation or chemical synthesis to distinguish the chemical compound from the contaminants.
  • “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • A“selective” inhibitor of a kinase means that a compound has at least a 3 -fold IC50 difference, e.g., at least lO-fold, 20-fold, 30-fold, 50-fold, lOO-fold, 300-fold, lOOO-fold, or at least 10000-fold IC50 difference, of one kinase over another kinase.
  • a compound selective for MEK1 over MEK3 has at least a 3 -fold lower MEK1 IC50 as compared to its MEK3 IC50.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • p is 0 or 1;
  • X is H or Ci-C 6 alkyl
  • Y is F, Cl, Br, I, N0 2 , CH , or CF 3 ;
  • R in each instance is independently F, Cl, Br, I, N0 2 , CH 3 , or CF 3 .
  • n is 1 or 2.
  • m can be 2.
  • n is 1 or 2.
  • n can be 2.
  • p is 0. In some embodiments, p is 1.
  • X is H or Ci-C 3 alkyl. In some embodiments, X is H or CH 3 . For example, X can be H.
  • Y is F, Cl, Br, I, CH 3 , or CF 3 . In some embodiments, Y is F, Cl, Br, I, or CH 3 . In some embodiments, Y is F, Cl, Br, or I. In some embodiments, Y is F or I.
  • R in each instance is independently F, Cl, Br, I, CH 3 , or CF 3 . In some embodiments, R in each instance is independently F, Cl, Br, I, or CH 3 . In some embodiments, R in each instance is independently F, Cl, Br, or I. In some embodiments, R in each instance is independently F or I.
  • the compound of Formula I is URML-3881 or a
  • Exemplary MEK inhibitor EIRML-3881 (also known as N-(l, l-dioxidothiomorpholino)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide) has the structure:
  • URML-3881 has physicochemical properties comparable to known MEK inhibitors trametinib and cobimetinib as shown in the table below. The predicted values were calculated using ChemDraw software (PerkinElmer Informatics, Inc.).
  • EIRML-3881 is a chemically a di-substituted hydrazine.
  • An amino group linked to thiazane ring distinguishes EIRML-3881 from other MEK inhibitors.
  • N-amino group spares the thiazane ring nitrogen in basic form whereas a similar structure of other MEK inhibitors carry an amidic nitrogen that has no basic character left.
  • the basic nitrogen present in ETRML-3881 enables it to be converted into a variety of salt forms whereas this feature is absent in the MEK inhibitors described by others.
  • ETRML-3881 has higher polar surface area and lower cLogP than the compound shown below.
  • the compound of Formula I is selective for MEK1 and/or MEK2.
  • the compound is selective over other MEK isoforms, e.g., MEK3 and/or MEK5.
  • the compound is selective over other kinases, e.g., one or more of EGFR, ERK1, VEGFR2, RAF1, MAPK14, and KSR1.
  • the compounds as described herein may be prepared and/or formulated as
  • compositions or when appropriate as a free base.
  • Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids. For example, a compound that contains a basic nitrogen may be prepared as a
  • Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfon
  • compositions comprising the compounds disclosed herein, or
  • pharmaceutically acceptable salts thereof may be prepared with one or more pharmaceutically acceptable excipients which may be selected in accord with ordinary practice.
  • the compound can be administered as salt of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid,
  • Disintegrants include, but are not limited to croscarmellose sodium, crospovidone, alginic acid, carboxymethylcellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate, partially hydrolysed starch, sodium carboxymethyl starch and starch. Preference is given to croscarmellose sodium and/or cross-linked polyvinylpyrrolidone, more preference is given to croscarmellose sodium.
  • Binders include, but are not limited to hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), microcrystalline cellulose, acacia, alginic acid, carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxaethylcellulose, ethylhydroxyethylcellulose, polyvinyl alcohol, polyacrylates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, polyvinyl pyrrolidone and pregelatinized starch.
  • hypromellose hydroxypropyl methylcellulose, HPMC
  • polyvinylpyrrolidone Preference is given to a hydrophilic binder which are soluble in the granulation liquid, more preference is given to hypromellose (hydroxypropyl methylcellulose, HPMC) and/or polyvinylpyrrolidone. In some preferred examples hypromellose is used.
  • a significant advantage of the invention is that the compound is useful and suitable for oral delivery.
  • the compound itself is basic and a simple salt, e.g., phosphate salt form, renders the compound soluble in aqueous media enabling it to be suitable for oral administration to cancer patients.
  • Tablets may contain excipients including glidants, fillers, binders and the like.
  • Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic. All compositions may optionally contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 6 th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin,
  • the composition is provided as a solid dosage form, including a solid oral dosage form.
  • compositions include those suitable for various administration routes, including oral administration.
  • the compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g ., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients.
  • the compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 2 I st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.
  • compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • the pharmaceutical composition is a tablet.
  • compositions disclosed herein comprise one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient and optionally other therapeutic agents.
  • Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • excipients which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia
  • lubricating agents such as magnesium
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient varies from about 5 to about 95% of the total compositions (weightweight).
  • a method of treating or reducing the severity of a cancerous condition comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is an ovarian cancer, e.g., an epithelial ovarian cancer such as CCOC.
  • Cancers that can be treated or prevented by the methods of the disclosure include solid tumors and lymphomas, including but not limited to adrenal cancer, bladder cancer, bone cancer, brain cancer, breast cancer, colon cancer, colorectal cancer, eye cancer, head-and-neck cancer, kidney cancer such as renal cell carcinoma, liver cancer, lung cancer such as non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer such as squamous cell carcinoma and melanoma, thyroid cancer, uterine cancer, vaginal cancer, and myeloma such as multiple myeloma.
  • the cancer can be naive, or relapsed and/or refractory.
  • the compound of the disclosure may be employed with other therapeutic methods of cancer treatment.
  • combination therapy with trastoxin may be employed with trastoxin
  • chemotherapeutic, hormonal, antibody, surgical and/or radiation treatments are used.
  • cancer medicaments include intercalating substances such as anthracycline, doxorubicin, idarubicin, epirubicin,and daunorubicin; topoisomerase inhibitors such as irinotecan, topotecan, camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone, amsacrine, ellipticines and aurintricarboxylic acid; nitrosourea compounds such as carmustine (BCNU), lomustine (CCNU), and streptozocin; nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine, bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamid and ifosfamide; alkyl sulfonates such as busulfan and treosulfan; alkylating agents such as procarbazin, dacarbacycline
  • a compound of Formula I described herein can be combined with a platinum analogue to treat ovarian cancer.
  • a platinum analogue such as cisplatin to treat ovarian cancer, e.g., clear cell ovarian cancer.
  • Example 2 MEK inhibition by URML-3881 in cancer cells
  • the mitogen activated protein kinase (MAPK) pathway is vita! to the survival of tumor cells and is an appealing potential target in cancer therapeutics. It is a signaling cascade initiated by the activation of receptor tyrosine kinases at the cell surface. After this initial step, intracellular kinases are activated sequentially leading to a phosphorylated kinase entering the nucleus where it regulates several processes including transcription and proliferation.
  • MAPK pathway involves Ras, Raf, MEK, and ERK and is known to play a role in tumor cell survival, proliferation, migration and angiogenesis. The role of MAPK pathway signaling in CCQC is poorly defined.
  • VEGF Vascular endothelial growth factor
  • EGFR epidermal growth factor receptor
  • MET hepatocyte growth factor receptor
  • this pathway is known to confer a chemotherapy resistant phenotype to tumor cells by mediating pro- survival signaling.
  • MEK inhibition has been shown to overcome platinum- chemotherapy resistance in several cancer cell types.
  • the ability of the MAPK pathway to contribute to cytotoxic escape makes it a candidate for combination treatment with chemotherapy in CCGC.
  • ES-2 was purchased from ATCC (CRL-1978). ES-2 was grown in
  • FBS supplemented McCoy media (Gibco, 16600-082) while all other cell lines were grown in FBS supplemented RPMI (Gibco, 22400-089).
  • FIG. 6A A schematic of synthesis is shown in FIG. 6A.
  • 3((2-fluoro-4 ⁇ iodopheny!amino)isonicotinic acid [1] [Ark Pharm Inc, Catalog No: AK118913] (0.1 mM) was coupled with 4- Aminothiomorpholine 1,1-Dioxide [2] [TCI Inc, A1798] (0.1 mM) in dry dichioromethane (10 mL) using DCC (Sigma Aldrich, Cat No: 36650), (0.12mM).
  • Isonicotinic acid [2] was stirred with DCC at 0°C in argon atmosphere for 10 minutes, a white suspension was formed.
  • Amine [2] was added and a catalytic amount of dimethyl aminopyridine (DMAP) (Sigma Aldrich, 39405) was added.
  • DMAP dimethyl aminopyridine
  • the reaction mixture was stirred overnight over a temperature range of OoC to room temperature.
  • the precipitated product was filtered and washed repeatedly with hexane (4x5niL) and dried under vacuum.
  • the final product, URML-3881 was synthesized multiple times in over 60% yields and was characterized by mass spectrometry.
  • the polar surface area, molar mass, LogP, eLogP and LogS of drugs were predicted using the property prediction feature of ChemDraw software.
  • kinases inhibition studies were performed by Reaction Biology Corp. In brief, purified kinases were incubated with known substrate, radiolabeled ATP and test drug or a predetermined reference compound. Enzyme activity was then determined by the presence of radiolabeled- phosphorylated substrate and calculated as a percentage of control. hn m unohi stochem i stry
  • a human ovarian tumor array was purchased from US Biomax (OV801 1).
  • the paraffin embedded slides were baked, deparaffmized in Americlear (Adwin Scientific, 72060044), and rehydrated in decreasing concentrations of ethanol.
  • Antigen retrieval was performed by- incubation in heated Dako target retrieval solution.
  • COCC cell lines such as OVMANA OVAS, OVTOKO, HCH-1, RMG-1, and ES-2 was determined after drag treatment using the 96 ® Aqueous-One-Solution Assay (Promega, G3580). Briefly, 5x10 s cancer cells were exposed to serial dilutions of URML- 3881 and incubated at 37°C for 24 hours. Media was then replaced with MTS reagent (1 : 10 dilution) and incubated for 2 hours. Absorbance was measured at 490 nm on a Bio-Rad iMARK microplate reader.
  • Annexin V Apoptosis Detection Kit (eBioscience, 88-8007) was used. In brief, 5 x 10 s OVMANA cells/well were plated and allowed to adhere, then the media was replace with fresh complete media containing URML-3881 (5 or 20 mM) or DMSO control, and incubated for 24 hours at 37°C. in order to avoid losing dead/dying cells, the media was collected and centrifuged and the adherent cells were collected by trypsinization and combined with the nonadherent cells. Cells were stained with annexin-V-APC, followed by 7- A AD according to the manufacturer’s instructions. Cells were then immediately analyzed by flow cytometry ' on a BD LSR Fortessa cytometer.
  • Proliferation of cells was determined by BrdU incorporation using a Ceil Proliferation Assay Kit (Cell Signaling Technology, 6813). 5x10 s w ? ere plated into a 96 well flat bottom plate and allowed to adhere, serial dilutions of URML-3881 or DMSO control, and BrdU were added to wells. Cells were incubated for 48 hours at 37°C, and then washed, fixed, denatured and stained with anti-BrdU-HRP according to manufacturer’s instructions. TMB substrate exposure time was 30 minutes, then stop solution was added and the absorbance was measured at 450 nM on a Bio-Rad iMARK microplate reader. Experiments were performed in replicates of 9. Data are expressed as the mean percentage ( ⁇ standard deviation) compared to control (DMSO) treated cells.
  • NOD scid gamma (NSG) mice were injected subcutaneously in the right flank with !xlO 6 QVMANA cells in 100 m ⁇ of matrigel (Coming, 356235). Tumors were allowed to establish for 8 weeks until they averaged approximately 100 mm3 in volume and animals were randomized.
  • Treatment with URML-3881 was delivered daily via oral gavage for 21 days at either 10 mg/kg dosing or 30 mg/kg dosing (PBS control).
  • PBS control When administered in the combination groups, cispiatin chemotherapy or control (PBS) was started 24 hours after URML-3881 treatment and was given intraperitoneally every 7 days (4 mg/kg) for 3 doses. Animals were monitored for signs of distress at least twice weekly throughout the course of the experiment. Tumor volume and animal weight was recorded weekly.
  • MAPK activity is elevated in CCQC
  • MAPK pathway overexpression in cancer is known to enhance proliferation and angiogenesis, thereby promoting tumor growth.
  • the importance of the MAPK pathway has been shown in other HOC subtypes, such as low-grade serous carcinomas which often cany a KRAS mutation.
  • RAS/RAF activating mutations are rare in CCOC
  • overexpression of MET, VEGF and EGFR, all which signal through the MAPK pathway, is frequently identified [4]
  • ERK is the substrate of MEK, and when activated by phosphorylation, it is considered to be a crucial effector in the MAPK pathway. Consequently, phosphorylated-ERK (pERK) levels are commonly used to quantitate MAPK pathway activity.
  • URML- is a selective MEK 1/2 inhibitor
  • MEK inhibitor URML-3881 (Fig. 2A), as selective, e.g., specific MEK1/2 inhibitor, was developed as described herein.
  • This class of drugs has been plagued by issues such as poor solubility and high molecular weight which lead to suboptimal
  • URML-3881 is a disubstituted hydrazine, carries a tertiary ' nitrogen that is basic, and can be salted variously to produce a salt form that is characterized by enhanced solubility and serum availability characteristics.
  • Other MEK inhibitors carry a metabolically less stable side chains.
  • URML-3881 has been designed to possess optimized drug-like qualities compared to existing MEK inhibitors in an effort to enhance pharmacokinetics and pharmacodynamics. These qualities are associated with significant advantages including including improved predicted solubility and a smaller molar mass. Additionally, URML-3881 structurally incorporates a tertiary nitrogen (Fig. 2A), that when converted to salt forms enhances its aqueous solubility.
  • Preferred salts are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesuiphonic acid, trifluoromethanesuifonic acid, benzenesulfonic acid, p-toluenesul tonic acid (tosylate salt), 1 -naphtha!
  • enesu!fonic acid 2-naphthalenesulfonic acid, acetic acid, triflu oroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acetic acid, and mandelic acid, lysine, phosphate, and/or camphor sulphonic acid (R and S and racemic mixture).
  • URML-3881 is a potent inhibitor of MEK 1/2 (Fig. 2B), with an IC50 of 30 tiM in a cell-free kinase inhibition assay. This assay also established the drug’s specificity for MEK 1 and 2; showing negligible or no detectable inhibitory function amongst a panel of other kinases including MEK 3 and MEK 5, which are activated in alternative MAPK signaling pathways.
  • URML-3881 inhibits CCOC MEK activity in vitro
  • URML-3881 inhibits CCOC viability both by induction of apoptosis and inhibition of proliferation
  • URML-3881 The ability of URML-3881 to inhibit tumor cell viability was determined. 20 mM of drug resulted in a significant reduction in the viability of 6 human-derived CCOC cell lines compared to a vehicle/excipient, e.g., a DMSO control (Fig. 3 A). This inhibition of CCOC viability was determined to be dose-dependent in 48 hour cell co-cultures with serial drug dilutions (Fig. 3B), with some cell lines showing a significant reduction in viability at concentrations as low as 1.25 mM.
  • pPEA-15 regulates the ability of ovarian cancer ceils to respond to MEK inhibition.
  • pPEA- 15 levels were assessed in various CCOC cell lines (isolated from different patients), and there was no clear correlation to MEK inhibitor response (Fig. 3C).
  • OVMANA was the most sensitive cell line and did not have higher pPEA-15 levels.
  • MAPK pathway is involved in both ceil survival and proliferation, experiments were carried out to determine which process was most impacted by URML-3881. Proliferation was determined by BrdU incorporation and all doses of drug tested (from 0.625 mM to 20 mM) caused a comparable modest reduction in tumor cell proliferation of between 15 and 30%, in a manner that did not seem to be dose-dependent (Fig.
  • URML-3881 is useful in combination therapy and may be useful/effective as a single-agent at certain doses. URML-3881 is useful in other cancer types as a single-agent as well as in combination with other chemotherapeutic drugs. URML-3881 (as a single-agent) shows in vitro responses against cell -lines derived from melanoma,
  • medulloblastoma and pancreatic cancer a combination of URML-3881 with cisplalin, paclitaxel, doxorubicin, topotecan, cyclophosphamide and/or other standard chemotherapies is useful against these and other cancers.
  • CCOC tumor bearing animals were treated with a single-bolus of 30 mg/kg URML-3881 and sacrificed 2.5 hours later. This timepoint was chosen based on the known short Tmax values of other MEK inhibitor compounds . Tumors were harvested and p- ERK level was determined by western blot. As expected, treatment with URML-3881 reduced p- ERK in tumors (Fig. 4A), thus confirming in vivo efficacy as a MEK inhibitor. Animals were then treated with URML-3881 at doses of either 10 mg/kg or 30 mg/kg daily (by oral gavage) for 21 days and tumor volumes were measured throughout. While URML-3881 was well tolerated by the animals at both doses, as evidenced by stable weight (Fig. 4B), it was not observed to induce tumor regression or delaying tumor growth at the doses testedfFig. 4C).
  • Platinum-based chemotherapy a staple in ovarian cancer treatment regimens increase ovarian cancer's reliance on the pro-survival MAPK pathway.
  • the role of URML-3881 as a combinatorial agent with platinum chemotherapy was evaluated. There is an increase in MAPK pathway activity in CCOC upon exposure to platinum chemotherapy (10 and 30 mM), 5/6 cell lines (Fig. 5A). The baseline p-ERK in OVAS was very faint and did not clearly change with chemotherapy. Dual drug culture experiments were performed in which cells were pre-treated with URML-3881 for 24 hours and then exposed to cisplatin chemotherapy . URML-3881 was able to abrogate chemotherapy-induced MAPK signaling (Fig. 5B) and reduce tumor cell viability (Fig.
  • CCOC is characterized by overactivity of the PI3K/AKT pathway due to mutations in ARID 1 A and PTEN.
  • the PI3K/AKT pathway is another intracellular signaling pathway that is known to enhance tumors genesis, and has extensive cross-talk with the MAPK pathway.
  • p-AKT levels in CCOC were assessed as a measure of PI3K activity, and a compensatory increase was found when the MAPK pathway was inhibited with URML- 3881 (Fig. 5B). This PI3K upregulation upon MAPK inhibition was still apparent in the presence of 10 mM of cisplatin but was less apparent at the 30 mM cisplatin concentration.
  • Cisplatin and URML-3881 reduces tumor size of CCOC in vivo and is well tolerated
  • URML-3881 + cisplatin was not significantly different from cisplatin alone (p ::: Q.09), likely due to variability within the cisplatin group.
  • Animal weight was recorded weekly and all treatment categories were well -tolerated with no significant changes between groups (Fig. 5F). There was a non-significant trend towards weight loss at day 21 in the URML-3881 + cisplatin group that improved weekly thereafter. Animals in all treatment groups retained baseline activity levels and showed no outward signs of distress.
  • MEK inhibition is useful as a treatment strategy in clear cell ovarian cancer and other cancer types such as MAPK over-expressing cancer types including pancreatic, lung, colon, and skin cancer. While MEK inhibition with URML-3881 showed promising in vitro activity as a single-agent, in vivo activity as a single-agent was not observed at the tested doses and dose schedule. When combined with cisplatin, URML-3881 was shown to inhibit prosurvival MAPK signaling and result in significant and long-lasting tumor regression, while cisplatin alone appeared to have no effect. Therefore, MEK inhibition with URML-3881 as a chemotherapy is useful for sensitizing adjunct to clear cell ovarian cancer treatment and represents a superior and advantageous method compared to earlier protocols.
  • the MAPK and PBK/mTOR pathways cross-talk and co-regulate one another.
  • CCQCs typically possesses heightened baseline activity of the PBK/mTOR pathway due to a high frequency of AR ID la and PTEN mutations.
  • One possible reason for the lack of observed efficacy of single-agent URML-3881 in vivo is compensatory upregulation of R ⁇ 3K activity.
  • An increase in PI3K activity was observed after MAPK inhibition with URML- 3881 in vitro , and in the chemotherapy combination group, the addition of high dose cisplatin also caused PI3K upregulation.
  • the data described herein provides evidence that combination MEK inhibition and cispiatin is effective against chemotherapy-resistant clear cell ovarian cancer.
  • This treatment strategy is associated with significant advantages for a disease that has limited therapeutic options and carries very poor survival rates in the advanced or recurrent setting.
  • These findings are applicable to the treatment of thousands of patients with many other cancer subtypes including cancers that have a high frequency of MAP K pathway activating mutations such as melanoma, lung cancer, ovarian cancer, colon cancer and pancreatic cancer.
  • MAPK overactivity and chemotherapy resistance are prominent features amongst highly fatal malignancies across cancer types.

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Abstract

La présente invention concerne des composés, des compositions et des méthodes de traitement de cancers à l'aide d'un inhibiteur de la MAPK/ERK kinase (MEK), en particulier des dérivés de l'hydrazine.
PCT/US2019/023420 2018-03-22 2019-03-21 Inhibition de mapk/erk pour le traitement du cancer de l'ovaire et d'autres cancers WO2019183385A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2006045514A1 (fr) * 2004-10-20 2006-05-04 Applied Research Systems Ars Holding N.V. Derives de 3-arylamino pyridine
WO2007108947A2 (fr) * 2006-03-16 2007-09-27 Women And Infants Hospital Of Rhode Island, Inc. Composes de nitrofurane utilises dans le traitement du cancer et de l'angiogenese
WO2012168884A1 (fr) * 2011-06-09 2012-12-13 Novartis Ag Dérivés de sulfonamide hétérocyclique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006045514A1 (fr) * 2004-10-20 2006-05-04 Applied Research Systems Ars Holding N.V. Derives de 3-arylamino pyridine
WO2007108947A2 (fr) * 2006-03-16 2007-09-27 Women And Infants Hospital Of Rhode Island, Inc. Composes de nitrofurane utilises dans le traitement du cancer et de l'angiogenese
WO2012168884A1 (fr) * 2011-06-09 2012-12-13 Novartis Ag Dérivés de sulfonamide hétérocyclique

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