WO2024246852A2 - Méthode de traitement de maladies fibrotiques à l'aide d'un inhibiteur de protéine kinase - Google Patents

Méthode de traitement de maladies fibrotiques à l'aide d'un inhibiteur de protéine kinase Download PDF

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WO2024246852A2
WO2024246852A2 PCT/IB2024/055335 IB2024055335W WO2024246852A2 WO 2024246852 A2 WO2024246852 A2 WO 2024246852A2 IB 2024055335 W IB2024055335 W IB 2024055335W WO 2024246852 A2 WO2024246852 A2 WO 2024246852A2
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fibrosis
compound
cancer
agent
pharmaceutically acceptable
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WO2024246852A3 (fr
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Muralidhara Ramachandra
Shekar S CHELUR
Saravanan Thiyagarajan
Payel Das
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Aurigene Oncology Ltd
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Aurigene Oncology Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

Definitions

  • VEGF vascular endothelial growth factor
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • DDR discoidin domain receptor
  • cytokines chemokines, caspases, and the like and therefore can serve as targets for potential anti-fibrotic drugs.
  • fibrosis can lead to long-term complications and impair the function of affected organs (Boulter et al., BJC 2021).
  • Chronic inflammation and fibrosis in certain organs, such as the liver (cirrhosis) or lungs (pulmonary fibrosis) can increase the risk of developing cancer.
  • the tissue damage and repair processes associated with fibrosis can create a microenvironment that promotes the initiation and progression of cancer (Wu et al., Cancers 2022).
  • the treatment of fibrosis encompasses both anti-fibrotic and anti-inflammatory medications.
  • Anti-inflammatory medication includes corticosteroids like prednisone and various immunosuppressants.
  • Anti-fibrotic medication includes nintedanib and pirfenidone.
  • Nintedanib acts by blocking multiple signaling pathways in the body. It blocks receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs).
  • RTKs receptor tyrosine kinases
  • nRTKs non-receptor tyrosine kinases
  • the RTKs inhibited by the nintedanib include those involved in the growth and development of cells (PDGFR, FGFR, VEGFR).
  • Non-receptor tyrosine kinases (nRTKs) such as Lek, Lyn, and Src kinases were also inhibited by nintedanib.
  • Nintedanib attaches to specific parts of these molecules, preventing them from sending signals (USFDA label).
  • the present application is based on an unexpected technical effect that Compound 1 can be used to effectively treat or delay the progression of fibrosis, in particular, idiopathic pulmonary fibrosis (IPF) which is a rare, progressive illness of the respiratory system.
  • IPF idiopathic pulmonary fibrosis
  • Example 1 compared to known drugs pirfenidone and nintedanib, it is unexpected to find that Compound 1 exhibits dose dependent inhibition of P-catenin reporter activity. As such, compound 1 specifically modulates the Wnt/p-catenin pathway through DDR1 and SIK2.
  • Compound 1 exhibits superior ability to downregulate p-LRP6 (low-density lipoprotein receptor-related protein 6), p-HDAC 4/5/7 (histone deacetylase 4/5/7), and c-Myc when compared to known SIK2 and DDR1 inhibitors.
  • p-LRP6 low-density lipoprotein receptor-related protein 6
  • p-HDAC 4/5/7 histone deacetylase 4/5/7
  • c-Myc when compared to known SIK2 and DDR1 inhibitors.
  • Compound 1 demonstrates compelling efficacy in the pulmonary fibrosis model even compared to the known drug pirfenidone, which offers a significant opportunity for this compound in fibrosis, cancer-associated fibrosis, or fibrotic cancer.
  • the present invention provides a method of treating or delaying the progression of fibrosis in a subject comprising administering to the subject a compound represented by formula (I),
  • FIG. 1A illustrates the inhibition percentage of fibrosis marker at various concentrations of Compound 1 in reporter assay in the HCT-116 cell line.
  • FIG. IB illustrates the inhibition percentage of fibrosis marker at various concentrations of pirfenidone in reporter assay in the HCT-116 cell line.
  • FIG. 1C illustrates the inhibition percentage of fibrosis marker at various concentrations of nintedanib in reporter assay in the HCT-116 cell line.
  • FIG. ID illustrates the inhibition percentage of fibrosis marker at various concentrations of imatinib in reporter assay in the HCT-116 cell line.
  • FIG. IE illustrates the inhibition percentage of fibrosis marker at various concentrations of sunitinib in reporter assay in the HCT-116 cell line.
  • FIG. IF illustrates the inhibition percentage of fibrosis marker at various concentrations of erdafitinib in reporter assay in the HCT-116 cell line.
  • FIG. 2A illustrates the layers of the transfer cassette for Western blot.
  • FIG. 2B illustrates the arrangement of the transfer tank.
  • Fig. 2C illustrates the Western blotting of p-LRP6 and p-HDAC4/5/7 with Compound 1, ARN- 3236, and DMSO.
  • Fig. 2D illustrates the Western blotting of c-Myc and IL- 18 with Compound 1, DDR1-IN-1, and DMSO.
  • FIG. 3A illustrates the change in albumin levels in C57BL/6 mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days.
  • Compound 1 10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day
  • PF pirfenidone
  • FIG. 3B illustrates the change in total protein levels in C57BL/6 mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days.
  • Compound 1 10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day
  • PF pirfenidone
  • FIG. 4A illustrates the change in TGF-P levels in C57BL/6 mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days.
  • Compound 1 10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day
  • PF pirfenidone
  • FIG. 4B illustrates the change in interleukin-6 (IL-6) levels in C57BL/6 mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days.
  • IL-6 interleukin-6
  • FIG. 4C illustrates the change in tumour necrosis factor-a (TNF-a) levels in C57BL/6 mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days.
  • TNF-a tumour necrosis factor-a
  • FIG. 5 illustrates the change in the lung histological characteristics in C57BL/6 mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days.
  • Compound 1 10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day
  • PF pirfenidone
  • FIG. 6A illustrates the change in the histological characteristics by Picrosirius Red staining of lung sections of mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days.
  • Compound 1 10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day
  • PF pirfenidone
  • FIG. 6B illustrates the change in the percentage of fibrotic area of mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days, where ****p ⁇ 0.0001 vs NC, ###p ⁇ 0.001 and ####p ⁇ 0.0001 vs DC. NC-Normal control, DC- Disease control, PF -Pirfenidone (200 mg/kg).
  • FIG. 7A illustrates the change in the histological characteristics by Masson’s Trichrome staining of lung sections of mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days.
  • FIG. 7B illustrates the change in the percentage of fibrotic area of mice that received Compound 1 (10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) and pirfenidone (PF) (200 mg/kg/day) at various treatment days, where ****p ⁇ 0.0001, #p ⁇ 0.05, ####p ⁇ 0.0001.
  • the present invention provides a method of treating or delaying the progression of fibrosis in a subject comprising administering to the subject a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound for use in treating or delaying the progression of fibrosis, wherein the compound is represented by formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention provides use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or delaying the progression of fibrosis.
  • the compound of formula (I) is an oral, selective kinase inhibitor targeting DDR1, SIK2, and related RTKs (FGFR, VEGFR, PDGFR, and RET).
  • the selectivity profile of the compound of formula (I) makes it suitable for the treatment or delay in the progression of fibrosis and a wide variety of cancers.
  • the fibrosis is mediated by Wnt/Beta-catenin signaling pathway.
  • the fibrosis is mediated by collagen/ECM signaling pathway.
  • the fibrosis is mediated by Discoidin domain receptor 1 (DDR1).
  • DDR1 Discoidin domain receptor 1
  • the fibrosis is mediated by Salt-inducible kinase 2 (SIK-2).
  • SIK-2 Salt-inducible kinase 2
  • the fibrosis is mediated by both Discoidin domain receptor 1 (DDR1) and Salt-inducible kinase 2 (SIK-2).
  • DDR1 Discoidin domain receptor 1
  • SIK-2 Salt-inducible kinase 2
  • the fibrosis is one or more selected from eye fibrosis, heart fibrosis, hepatic fibrosis, lung fibrosis, pancreas fibrosis, renal fibrosis, bone marrow fibrosis, and skin fibrosis.
  • the fibrosis is one or more selected from pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), interstitial lung diseases (ILDs), chronic fibrosing interstitial lung diseases (ILDs) with aprogressive phenotype, systemic sclerosis-associated interstitial lung disease (SSc-ILD), radiation-induced lung injury, bridging fibrosis, liver cirrhosis, non-alcoholic hepatosteatosis (NASH), non-alcoholic fatty liver disease (NAFLD), atrial fibrosis, skeletal muscle fibrosis, myocardial fibrosis, endomyocardial fibrosis, myocardial infarction related fibrosis, glial scar, ocular fibrosis, arterial stiffness, arthrofibrosis, inflammatory bowel diseases, crohn's disease, dupuytren contracture, mediastinal fibrosis, intestinal fibrosis, mye
  • the fibrosis is one or more selected from pulmonary fibrosis, idiopathic pulmonary fibrosis, interstitial lung disease (ILDs), and systemic sclerosis- associated interstitial lung disease (SSc-ILD).
  • the fibrosis is pulmonary fibrosis.
  • the pulmonary fibrosis is idiopathic pulmonary fibrosis.
  • the fibrosis is interstitial lung disease (ILDs).
  • ILDs interstitial lung disease
  • the fibrosis is systemic sclerosis-associated interstitial lung disease (SSc-ILD).
  • SSc-ILD systemic sclerosis-associated interstitial lung disease
  • the fibrosis is characterized by aberrant fibroblast proliferation and extracellular matrix deposition in the tissue of a subject.
  • the fibrosis is further characterized by an inflammation in the tissue.
  • the inflammation is acute or chronic inflammation.
  • the inflammation is mediated by one or more cytokines selected from the group consisting of Tumor Necrosis Factor-alpha (TNF-a), Interleukin-6 (IL-6), and Interleukin-ip (IL-Ip).
  • TNF-a Tumor Necrosis Factor-alpha
  • IL-6 Interleukin-6
  • IL-Ip Interleukin-ip
  • pulmonary fibrosis is characterized by the presence of one or more conditions selected from an aberrant deposition of an extracellular matrix protein in a pulmonary interstitium, an aberrant promotion of fibroblast proliferation in the lung, an aberrant induction of myofibroblast differentiation in the lung, and an aberrant promotion of attachment of myofibroblasts to an extracellular matrix compared to a normal healthy control subject.
  • the fibrosis is cancer-associated fibrosis or fibrotic cancer.
  • the cancer-associated fibrosis or fibrotic cancer is biliary cancer, cholangiocarcinoma, bladder cancer, colorectal cancer, colon cancer, rectal cancer, colorectal adenocarcinoma, brain cancer, meningioma, glioma, astrocytoma, oligodendroglioma, medulloblastoma, breast cancer, adenocarcinoma of the breast, inflammatory carcinoma of the breast, papillary carcinoma of the breast, medullary carcinoma of the breast, kidney cancer nephroblastoma/Wilms' tumor, renal cell carcinoma, cervical cancer, squamous cell carcinoma of the cervix, cervical adenocarcinoma, gastric cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, head and neck squamous cell carcinoma, oral cancer, oral squamous cell carcinoma (OSCC), keloids, leukemia, acute lymph
  • the compound of formula (I) is in the form of hydrochloride (HC1) salt.
  • the molar ratio between the compound of formula (I) and hydrochloride is 1 : 1.
  • the hydrochloride (HC1) salt of the compound of formula (I) is in crystalline form.
  • the method of treating or delaying the progression of fibrosis further comprises administering an additional anti -fibrotic agent to the subject.
  • the additional anti-fibrotic agent is one or more selected from an agent that blocks TGF-P signaling, an agent that inhibits activation of plasminogen activator inhibitor- 1 promoter activity, an antibody that binds to TGF-P, an antibody that binds to TGF- P receptor I, II, or III, a kinase inhibitor, an agent that blocks connective tissue growth factor (CTGF) signaling, an agent that inhibits prolyl hydroxylase, an agent that inhibits procollagen C-proteinase, an agent that inhibits vascular endothelial growth factor VEGF, an agent that antagonizes TGF-P, an agent that antagonizes CTGF, and Corticosteroids.
  • CTGF connective tissue growth factor
  • the additional anti-fibrotic agent is one or more selected from pirfenidone, nintedanib, silymarin, pentoxifylline, colchicine, etanercept (embrel), infliximab (remicade), tocilizumab, prednisone, mycophenolate mofetil, mycophenolic acid, and azathioprine.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 50 mg to 400 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 80 mg to 350 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 90 mg to 300 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 50 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 100 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 150 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 200 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 250 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 300 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 350 mg. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 400 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject daily as a continuous regimen for a 21 -day cycle.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as an interrupted regimen for a 21 -day cycle.
  • the interrupted regimen comprises two weeks of daily administration followed by one week off.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject for repeated 21 -day cycles till the complete remission of the disease.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in the range of 2 cycles to 10 cycles.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in the range of 2 cycles to 5 cycles.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in the range of 2 cycles to 4 cycles.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject for at least two 21 -day cycles.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject for at least one 21 -day cycle.
  • each cycle comprises 21 days of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • each cycle comprises 21 days of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof with interruption.
  • the interruption is in the range of 1 days to 7 days.
  • the subject is a mammal.
  • the subject is human.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to mice at a daily dose of 10 mg/kg/day to 60 mg/kg/day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to mice at a daily dose of 40 mg/kg/day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to mice at a daily dose of 20 mg/kg/day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to mice at a daily dose of 10 mg/kg/day.
  • the present invention provides a method of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a lung of a subject suffering from fibrosis.
  • the method of treating or delaying the progression of fibrosis comprising the step of administering to a lung of a subject suffering from fibrosis a therapeutically effective amount of compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • the compound for use in treating or delaying the progression of fibrosis comprising the step of administering to a lung of a subject suffering from fibrosis a therapeutically effective amount of compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • the compound of formula (I) is in the form of a solution.
  • the compound of formula (I) is in the form of suspension or nanosuspension.
  • the compound of formula (I) is in the form of a liposome formulation.
  • the compound of formula (I) is in the form of powder.
  • the compound of formula (I) is in the form of powder for inhalation.
  • the compound of formula (I) is administered through intratracheal, pulmonary, or oropharyngeal route.
  • the method further comprises an additional anti-fibrotic agent.
  • the additional anti-fibrotic agent is one or more selected from an agent that blocks TGF-P signaling, inhibits activation of plasminogen activator inhibitor- 1 promoter activity, an antibody that binds to TGF-P, an antibody that binds to TGF-P receptor I, II, or III, a kinase inhibitor, an agent that blocks connective tissue growth factor (CTGF) signaling, an agent that inhibits prolyl hydroxylase, an agent that inhibits procollagen C- proteinase, an agent that inhibits vascular endothelial growth factor VEGF, an agent that antagonizes TGF-P, an agent that antagonizes CTGF, and Corticosteroids.
  • CTGF connective tissue growth factor
  • the additional anti-fibrotic agent is one or more selected from pirfenidone, nintedanib, silymarin, pentoxifylline, colchicine, etanercept, infliximab, tocilizumab, prednisone, mycophenolate mofetil, mycophenolic acid, treprostinil, belumosudil, and azathioprine.
  • the additional anti-fibrotic agent is administered through oral, parenteral, intravenous, intraperitoneal, oropharyngeal, and pulmonary routes.
  • the present invention provides a composition for pulmonary administration.
  • the composition comprises a compound represented by a compound of formula (I) or a pharmaceutically acceptable salt thereof;
  • the composition is in the form of a solution.
  • the composition is in the form of suspension or nanosuspension.
  • the composition is in the form of a liposome formulation.
  • the composition is in the form of powder.
  • the composition is in the form of powder for inhalation.
  • the composition is administered orally, intratracheally, parenterally, intravenously, intraperitoneally, or oropharyngeally.
  • the composition is administered intratracheally or oropharyngeally.
  • the composition is administered oropharyngeally.
  • the composition is administered as a single dose.
  • the composition is administered as a plurality of doses.
  • the composition is administered as a plurality of doses over a period of time.
  • the period of time is a day.
  • the composition further comprises an additional anti-fibrotic agent.
  • the additional anti-fibrotic agent is one or more selected from an agent that blocks TGF-P signaling, inhibits activation of plasminogen activator inhibitor- 1 promoter activity, an antibody that binds to TGF-P, an antibody that binds to TGF-P receptor I, II, or III, a kinase inhibitor, an agent that blocks connective tissue growth factor (CTGF) signaling, an agent that inhibits prolyl hydroxylase, an agent that inhibits procollagen C- proteinase, an agent that inhibits vascular endothelial growth factor VEGF, an agent that antagonizes TGF-P, an agent that antagonizes CTGF, and Corticosteroids.
  • CTGF connective tissue growth factor
  • the additional anti-fibrotic agent is one or more selected from pirfenidone, nintedanib, silymarin, pentoxifylline, colchicine, etanercept (embrel), infliximab (remicade), tocilizumab, prednisone, mycophenolate mofetil, mycophenolic acid, treprostinil, belumosudil and azathioprine.
  • the present invention provides a method of preventing or slowing the progression of or treating disease, condition, or pathologic process characterized by aberrant fibroblast proliferation and extracellular matrix deposition in a tissue of a subject comprising administering to the subject in need thereof an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • pulmonary fibrosis results from an allergic reaction, inhalation of environmental particulates, smoking, a bacterial infection, a viral infection, mechanical damage to the lung of the subject, lung transplantation rejection, an autoimmune disorder, a genetic disorder, or a combination thereof.
  • the efficacy of compound 1 was evaluated by using in-vitro cellular reporter assay studies, western blot, and bleomycin-induced mouse model.
  • the studies confirmed that Compound 1 of the present disclosure, shows enhanced efficacy when compared to the pirfenidone, nintedanib, imatinib, sunitinib, and erdafitinib. Further, the histological studies show a decrease in fibrotic area, characterized by less collagen, suggesting that Compound 1 of the present disclosure is more effective in comparison with known compounds.
  • the term “subject” means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats, and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • an “effective amount” of the Compound of formula (I), or a pharmaceutically acceptable salt is an amount sufficient to provide a therapeutic benefit in preventing or slowing the progression of or treating disease, condition, or pathologic process characterized by aberrant fibroblast proliferation and extracellular matrix deposition.
  • the terms “therapeutically effective amount” and “effective amount” are used interchangeably.
  • the term “effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition.
  • an effective amount is an amount sufficient for eliciting therapeutic effects in the treatment of a fibrotic disease cancer (including lung fibrosis as further described herein).
  • An effective amount of the Compound of formula (I), a pharmaceutically acceptable salt thereof is generally in the range from 1 mg/kg to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 40 mg/kg of body weight per day.
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease/disorder characterized by aberrant fibroblast proliferation and extracellular matrix deposition in a tissue or improve the symptoms associated with the disease/disorder. Treatment may also be continued after symptoms have resolved, for example, to reduce the likelihood of or delay their recurrence.
  • Example - 1 In-vitro cellular reporter assay studies
  • DDR1 is a tyrosine kinase receptor activated by collagen and modulates the Wnt/p-catenin pathway through phosphorylation of its downstream target, BCR. The activation of this pathway leads to the production of key fibrotic marker TGF-p.
  • Compound 1 was compared with pirfenidone and nintedanib (FDA- approved drugs for idiopathic pulmonary fibrosis) and Imatinib, Sunitinib, and Erdafitinib (drugs approved as multi-tyrosine kinase inhibitors).
  • the HCT-116 cells were transfected with T-cell factor (TCF) reporter plasmid driving the expression of firefly luciferase reporter and subsequently treated with different concentrations of Compound 1, pirfenidone, nintedanib, imatinib, sunitinib, erdafitinib and % inhibition in a reporter activity was measured 24 h post-treatment.
  • TCF T-cell factor
  • the Renilla substrate (Dual-Glo® Stop & Gio® Substrate) was stored at -20°C.
  • the Renilla substrate (Dual-Glo® Stop & Gio® Substrate) (1 :100) was added to the Dual-Glo® Stop & Gio® Buffer just before adding to the cells.
  • LiCl lithium chloride
  • HCT-116 cells were seeded at a seeding density of 12000 cells/well in a 96-well plate in 90 pl of McCoy’s 5Amedium containing 10% FBS (Foetal Bovine Serum) and 1% Penstrep (Penicillin-Streptomycin). The cells were incubated at 37°C, 5% CO2 overnight. Day 2: Transfection
  • Opti-MEMTM I Reduced Serum Medium and FuGENE® HD Transfection Reagent were brought to room temperature (RT) and the transfection solution was prepared as per the volume and concentrations mentioned below
  • the plasmids were added to Opti-MEMTM I Reduced Serum Medium and vortexed. FuGENE® HD Transfection Reagent was then vortexed briefly and added directly to Opti-MEMTM I Reduced Serum Medium containing the plasmids in the ratio of 3: 1.
  • the solution was mixed well with 1 mL pipette and incubated at RT for 15 min. 5 pL of this solution was then added per well of cells (assay plate) and mixed well by pipetting. The assay plate was then gently swirled and incubated at 37 °C and 5% CO2 for 24 h.
  • the starting concentration for Compound 1 was 10 pM and serially diluted 3 -fold dilution with an 8-point dose-response curve (DRC).
  • the initial drug dilutions were made in 100% dimethyl sulfoxide (DMSO).
  • An intermediate dilution of 100X was made in McCoy’s 5 A containing 0.5mM LiCl and 10 pl of this intermediate solution was added to the cells to achieve a 10X dilution.
  • the starting concentration for pirfenidone was 10 mM and a 10-fold dilution of this compound was made to achieve a 5 -point dose response curve (DRC).
  • the initial drug dilutions were made in 100% DMSO.
  • An intermediate dilution of 100X was made in culture medium and 10 pl of this intermediate solution was added to the cells to achieve a 10X dilution.
  • the starting concentration for nintedanib was 1 pM and a 10-fold dilution of this compound was made to achieve a 5 -point dose response curve (DRC).
  • the initial drug dilutions were made in 100% DMSO.
  • An intermediate dilution of 100X was made in culture medium and 10 pl of this intermediate solution was added to the cells to achieve a 10X dilution.
  • the starting concentration for imatinib was 10 pM and a 10-fold dilution of this compound was made to achieve a 5 -point dose response curve (DRC).
  • the initial drug dilutions were made in 100% DMSO.
  • An intermediate dilution of 100X was made in culture medium and 10 pl of this intermediate solution was added to the cells to achieve a 10X dilution.
  • the starting concentration for sunitinib was 100 nM and a 10-fold dilution of this compound was made to achieve a 5 -point dose response curve (DRC).
  • the initial drug dilutions were made in 100% DMSO.
  • An intermediate dilution of 100X was made in culture medium and 10 pl of this intermediate solution was added to the cells to achieve a 10X dilution.
  • the starting concentration for erdafitinib was 10 nM and a 2-fold dilution of this compound was made to achieve a 5 -point dose response curve (DRC).
  • the initial drug dilutions were made in 100% DMSO.
  • An intermediate dilution of 100X was made in culture medium and 10 pl of this intermediate solution was added to the cells to achieve a 10X dilution.
  • the final DMSO concentration was maintained at 0.1%.
  • the cells were incubated for 24 hr at 37°C, 5% CO 2 .
  • Dual-Glo® Luciferase Reagent and Dual-Glo® Stop & Gio® Buffer were brought to room temperature.
  • 50 pL of Dual-Glo® Luciferase Reagent was added to each well and the assay plate was wrapped in an aluminium foil.
  • the plate was incubated on a shaker (100 rpm) at room temperature for 20 min and reading was taken using a Clariostar PLUS multimode plate reader to obtain a firefly luciferase signal.
  • Renilla substrate (Dual-Glo® Stop & Gio® substrate) was added to Dual-Glo® Stop & Gio® Buffer in the ratio of 1 : 100 then the mix was vortexed briefly and added 50 pl to each well of the assay plate.
  • the plate was wrapped in an aluminium foil and incubated again for 20 minutes on the shaker (100 rpm) at room temperature.
  • the luminescence reading was taken using a Clariostar PLUS reader to obtain renilla
  • the firefly luciferase signal was normalized to the renilla luciferase signal for each respective well to get the firefly signal per cell (normalization factor).
  • the percentage (%) reporter activity was calculated for each lane with respect to DMSO using the normalization factor obtained [normalized firefly signal/average DMSO firefly signal) *100], The Mean and SD of % reporter activity for each condition were calculated and the data was represented taking DMSO reporter activity to be 100%.
  • Compound 1 of the present disclosure was evaluated for its activity on the downstream targets of DDR1-SIK2 -Wnt/p-catenin pathway i.e. p-LRP6, p-HDAC 4/5/7 in a SIK2-overexpressing triple-negative breast cancer cell line, BT549, and c-Myc and IL- 18 in a DDR1 -overexpressing colorectal cancer cell line, HCT-116.
  • the activity of the compound of formula I was compared with the known DDR1 and SIK2 inhibitors i.e. ARN-3236 (SIK2 inhibitor) and DDR1-IN-1 (DDR1 inhibitor).
  • Compound 1 of the present disclosure was evaluated for its activity on the DDR1-SIK2 -Wnt/p-catenin pathway.
  • the activity was evaluated by detection/expression of biomarkers such as p-LRP6, p-HDAC 4/5/7 for SIK2; c-Myc for IL-18 for DDR1.
  • Tris pH 6.8 Buffer 25 mL: 3.94 gm of Trizma hydrochloride was dissolved in 15 mL Milli-Q water by placing it in a magnetic stirrer for approximately 1 hour. The pH was adjusted to 6.8 using concentrated NaOH and concentrated HC1 solutions. The buffer was mixed well after each pH adjustment. The volume was made up to 150 mL with Milli-Q water. The pH was checked again and adjusted to 6.8 with the addition of NaOH and HC1. It was mixed well and stored at RT.
  • SDS sodium dodecyl sulfate
  • 200 mL 20 gm of SDS crystals were dissolved in 125 mL of Milli-Q water and mixed well by shaking for 10 - 15 minutes. The solution was stored at RT overnight for the complete dissolution of the SDS crystals. The next day, the volume was made to 200 mL using Milli-Q water. The prepared solution was stored at RT.
  • Ponceau stain 0.1 gm of Ponceau powder was dissolved in 2.5 mL of glacial acetic acid. The stain was completely dissolved by adding 10 - 15 mL of Milli-Q water. Once completely dissolved, the volume was made to 50 mL with Milli-Q water. The prepared solution was stored at RT.
  • PBS To prepare 1000 mL of PBS, one sachet of PBS was emptied into a glass bottle and dissolved in 800 mL of HPLC grade water. The volume was made up to 1000 mL with water. The same was autoclaved and stored at RT inside the laminar hood.
  • Running buffer (per tank, per 4 gels) (1300 mL): 130 mL of 10X Tri s-Gly cine- SDS buffer was diluted in 1170 mL of Milli-Q water and mixed well. The solution was stored at RT.
  • Transfer buffer per tank with the use of ice pack (per 2 gels) (1500 mL): 150 mL of 10X Tris-Glycine buffer was diluted in 1050 mL of Milli-Q water. 350 mL of HPLC- grade methanol was added to it. The solution was stored in a cold room or -20°C freezer until use (must be used within 3 hours before crystallization of the solution).
  • IX TBST 1000 mL: 100 mL of 10X TBST solution was diluted in 900 mL of Milli- Q water and mixed well. 1000 pL of Tween -20 was added to it and mixed well until Tween-20 completely dissolved. The solution was stored at RT. The solution must be used within a day.
  • RPMI-1640 complete medium To 445 mL of RPML1640, 50 mL FBS and 5 mL of Penstrep were added. The prepared medium was stored at 2-8 °C. Human insulin (1 : 1000) was freshly added when the medium was used to culture cells.
  • HCT-116 cells ATCC
  • BT549 cells triple-negative breast cancer cell line running culture was maintained at 37°C and 5% CO2 in McCoy’s 5A complete medium and RPMI-1640 complete medium respectively in T-75 flasks.
  • McCoy 5A complete medium
  • RPMI-1640 complete medium respectively in T-75 flasks.
  • the media was aspirated, and the cells were washed with PBS followed by their trypsinization with 3 mL of IX Trypsin EDTA solution at 37 °C and 5% CO2 for 5 min.
  • the residual trypsin activity was neutralized with 10 mL of fresh medium.
  • the cell suspension was centrifuged at 1200 rpm for 5 min and the supernatant was discarded to obtain the cell pellet.
  • the cell pellet was resuspended in 1 mL of complete medium and cell density was determined by counting the number of cells.
  • the cells were treated with either 3 pM, 1 pM, 0.33 pM of Compound 1, and 4 pM of ARN-3236 (CAS No. 1613710-01-2) for BT549 and the same concentrations of Compound 1 and 1 pM of DDR1-IN-1 (CAS No. 1449685-96-4) for HCT-116.
  • the final DMSO concentration was 0.1%.
  • the plates were then gently swirled and incubated at 37 °C and 5% CO2 for 24 h.
  • the media from the cells were aspirated out and the cells were washed with PBS.
  • 60 pL of lysis buffer was added and cells were incubated on ice for 5 minutes. Following that, the cells were scrapped with a scraper on ice until all the cells were collected for lysis.
  • the cell lysates were transferred to 1.5 mL microcentrifuge tubes and incubated on ice for 20 min with occasional vortexing every 5 min. They were then sonicated for 30 sec, and then incubated on ice for 30 sec. This step was repeated twice. Following sonication, lysates were centrifuged at 15000 rpm at 4°C for 15 minutes. The supernatant containing protein was collected for further evaluation.
  • BSA bovine serum albumin
  • the absorbance of the samples was measured at 562 nm using a multi-plate reader, and the concentrations of the protein samples were measured using the slope obtained from the BSA standard curve.
  • the proteins were stored at -80°C until further evaluation.
  • Resolving solution (7.5%, for p-LRP6, p-HDAC 4/5/7): The following reagents were added in the following order. APS and TEMED were added only before adding the resolving gel solution into the gel casting compartment. They are all mixed well by gently inverting the centrifuge tube. The formation of air bubbles was avoided.
  • Resolving solution (12%, for IL-18, c-Myc): The following reagents were added in the following order. APS and tetramethylethylenediamine (TEMED) were added only before adding the resolving gel solution into the gel casting compartment. They are all mixed well by gently inverting the centrifuge tube. The formation of air bubbles was avoided.
  • APS and tetramethylethylenediamine (TEMED) were added only before adding the resolving gel solution into the gel casting compartment. They are all mixed well by gently inverting the centrifuge tube. The formation of air bubbles was avoided.
  • the resolving gel was immediately added to the gel casting compartment.
  • Stacking gel solution (5%): The following reagents were added in the following order. APS and TEMED were added only before adding the resolving gel solution into the gel casting compartment. They are all mixed well by gently inverting the centrifuge tube. The formation of air bubbles was avoided.
  • the stacking gel was immediately added to the gel casting compartment.
  • the gel casting setup was rested for 30 minutes until the gel solidified.
  • the IPA solution was then discarded by inverting the gel casting setup.
  • the comers were dabbed with tissue papers to remove any residual IPA.
  • 1 mL of HPLC grade water was layered on top of the resolving gel using a 1 mL pipette to ensure the removal of excess IPA.
  • the water was discarded by inverting the casting set and the corners were dabbed with tissue paper to remove any residual water.
  • the gels were gently placed in the running modules, followed by placing the nodules in the running tank aligning the anode and cathode electrodes.
  • the running tanks were filled with running buffers up to the 4-gel mark.
  • the inserted combs were then gently removed from the casted gel. It was ensured that the tanks were filled with running buffers.
  • the proteins were taken out from -80°C and thawed in an ice bath for approximately 5 minutes. To 50 pg of protein, IX Pierce Lane Marker Reducing Sample Buffer was added and the volume was made up to 25 mL by RIPA lysis buffer. The proteins were then boiled at 95°C for 10 minutes. The samples were then vortexed and given a short spin.
  • the PVDF membrane was submerged in methanol for approximately 1 minute. It was then placed in a prepared ice-cold transfer buffer. The transfer tank was filled with this ice-cold transfer buffer until the 4-gel mark and the ice packs were placed onto it. The components in the Western Blot cassette were arranged in a specific order, illustrated in FIG. 2A. The formation of air bubbles in between layers was avoided. The transfer cassette was placed in the trans-blot module.
  • the trans-blot was placed in the transfer tankaligning cathode and anode electrodes, illustrated in FIG. 2B.
  • the transfer tank was covered with the lid in proper alignment with the anode and cathode electrodes.
  • the electrodes were connected to the power pack.
  • the voltage was set to 70 V and it was run for 120 minutes. The entire process was carried out in the cold room.
  • the run button was pressed to start the transfer process. Tiny bubbles at the wire electrodes of the modules indicated the ongoing transfer process, it automatically stopped after 120 minutes.
  • the PVDF membrane was gently removed from the transfer cassette.
  • the membrane was submerged in methanol for approximately 1 minute. It was washed thrice with Milli-Q water, with 1 minute/wash. Ponceau stain was then added onto the membrane and it was stained for approximately 2 minutes until the protein bands were visible. The membrane was again washed with Milli-Q water to remove excess Ponceau and the membrane was checked for proper transfer of the proteins. It was then washed with Milli-Q water for approximately 1 minute per wash, followed by washing with previously used transfer buffer for approximately 5 minutes to completely de-stain the membrane from Ponceau.
  • the blocking buffer was collected and immediately 10 mL of required primary antibodies were added to each of the membranes. It was ensured that at any point the membrane wasn’t left dry.
  • the staining boxes were incubated on a platform rocker overnight in the cold room.
  • the primary antibody solutions were collected and stored in a freezer at -20°C.
  • the membranes were washed with 10 mL IX TBST buffer (Tris-buffered saline with 0.1% Tween® 20 Detergent) 5 times, with each wash being 25 minutes. After each wash, the TBST solution was discarded, and a fresh solution was added. 10 mL of secondary antibody was then added to the membranes, and they were incubated on the platform rocker for 2 hours at RT. The secondary antibodies were then discarded, and the membranes were again washed with 10 mL IX TBST buffer 5 times, with 25 min/wash.
  • IX TBST buffer Tris-buffered saline with 0.1% Tween® 20 Detergent
  • Example - 3 Anti-fibrotic effects in Mouse Bleomycin (BLM) Induced Pulmonary Fibrosis model
  • mice Six to eight-week-old male C57BL/6 N mice (specific-pathogen-free (SPF) grade, 20 g to 25 g) were acclimatized to experimental conditions and randomly distributed into 6 groups of 10 animals.
  • SPF specific-pathogen-free
  • G2 BLM disease control group (DC)
  • G3 BLM + Compound 1, 10 mg/kg/day
  • G5 BLM + Compound 1, 40 mg/kg/day
  • the Bleomycin (BLM) injection was used for induction of Pulmonary Fibrosis. Mice were oropharyngeally administered two doses of Bleomycin at 1.5 lU/mice (Days 0 and 2). All experiment animals were induced with BLM except the normal control group which were oropharyngeally administered with normal saline. The decrease in body weight after BLM lung installation is indicative of initiation of lung injury, and pro-inflammatory cytokines elevation due to severe inflammatory condition.
  • the animals were dosed with the indicated dose from Day 5 i.e. after 5 days of administration of bleomycin daily for 23 days.
  • Day 28 lung physiological parameters were evaluated by whole-body plethysmography.
  • Day 29 the animals were sacrificed and evaluated for lung morphological evaluation, lung biochemical evaluation, and histopathological evaluation.
  • PF pirfenidone
  • Compound 1 results in dose dependent effect on lung function parameters, lung morphology, lung weight index, BALF counts (total cell, lymphocytes, neutrophils population, albumin, and total protein levels (FIG. 3A & 3B)).
  • Compound 1 resulted in dose-dependent effect on albumin and total protein content in mice, illustrated in FIG. 3A and 3B. Effect of Compound 1 and Pirfenidone on IL-6, TNF-a, and TGF-P in bleomycin induced lung fibrotic mice a) TGF-P levels b) IL-6 levels c) TNF-a levels
  • the lung tissue pro-inflammatory cytokines mainly TGF-P, IL-6, and TNF-a levels indicate antifibrotic effects, illustrated in FIG. 4A, 4B, and 4C respectively.
  • the H&E staining of Compound 1 treated groups and pirfenidone (standard drug) clearly demonstrated dose dependent reduction in lung histological abnormalities in BLM- induced fibrotic lung sections. There was a significant increase in the extracellular matrix deposition and decreased alveolar spaces in fibrotic lung tissues.
  • the characteristic fibrotic features were found to be gradually reduced in a dose-dependently manner with Compound 1 treated groups and PF treated group with the maximum reduction in histological features observed with Compound 1 at 40 mg/kg/day dose group.
  • the Ashcroft scoring of lung fibrosis also indicated a similar kind of damage in the BLM group and protective effects in Compound 1 and PF treated animals, illustrated in FIG. 5.
  • the lung sections obtained from the mice after the completion of the study were stained with Picrosirius red staining (https://ihcworld.com/2024/01/26/sirius-red-staining-protocol- for-collagen/, last accessed on May 30, 2024) and the stained tissues were observed for the presence of collagen under a bright field and polarized microscope at 20X magnification, illustrated in FIG. 6 A and 6B.
  • Results are expressed as mean ⁇ SEM. ****p ⁇ 0.0001 vs NC, ###p ⁇ 0.001 and ####p ⁇ 0.0001 vs DC. NC-Normal control, DC- Bleomycin control, PF -Pirfenidone (200 mg/kg/day).

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Abstract

La présente divulgation concerne une méthode de traitement ou de ralentissement de la progression de la fibrose chez un sujet, comprenant l'administration du composé de formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci. La présente divulgation concerne également une méthode d'administration du composé de formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci à un poumon.
PCT/IB2024/055335 2023-06-01 2024-05-31 Méthode de traitement de maladies fibrotiques à l'aide d'un inhibiteur de protéine kinase Ceased WO2024246852A2 (fr)

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