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WO2024225750A1 - Utilisation, en tant qu'agent anticancéreux, d'inhibiteur de parp de nouvelle génération pour le traitement du cancer ayant une co-mutation atm et asxl1 - Google Patents

Utilisation, en tant qu'agent anticancéreux, d'inhibiteur de parp de nouvelle génération pour le traitement du cancer ayant une co-mutation atm et asxl1 Download PDF

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Publication number
WO2024225750A1
WO2024225750A1 PCT/KR2024/005536 KR2024005536W WO2024225750A1 WO 2024225750 A1 WO2024225750 A1 WO 2024225750A1 KR 2024005536 W KR2024005536 W KR 2024005536W WO 2024225750 A1 WO2024225750 A1 WO 2024225750A1
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cancer
atm
asxl1
compound
pharmaceutical composition
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Korean (ko)
Inventor
이원식
하경수
노은진
이명재
홍민주
박현웅
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Idience Co Ltd
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Idience Co 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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of next-generation PARP inhibitors as anticancer agents, and more particularly, to a pharmaceutical composition comprising a next-generation PARP inhibitor as an active ingredient for the treatment of cancers having ATM and ASXL1 co-mutations.
  • Poly(adenosine diphosphate ribose) polymerase or poly(ADP ribose) polymerase (PARP) is a family of enzymes involved in DNA repair, consisting of 18 members, including PARP-1, PARP-2, and PARP-3, located in the cell nucleus and involved in the repair of DNA damage.
  • PARP inhibitors have been used to target BRCA1/2-defective cells that undergo DNA single-strand breaks (SSBs).
  • Homologous recombination repair (HRR) mutations including BRCA mutations (BRCAm) are well-established predictive biomarkers for PARP inhibitor treatment in pancreatic cancer.
  • the BRCA1 or BRCA2 genes are responsible for homologous recombination-mediated repair of damaged double-stranded DNA.
  • SSBs DNA single-strand breaks
  • DSBs toxic double-strand breaks
  • the DNA-binding domains of both PARP-1 and PARP-2 contain two zinc finger motifs that facilitate the transport of repair enzymes to sites of DNA damage.
  • PARP-1 and PARP-2 catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to a nuclear receptor protein, resulting in the formation of ADP-ribose polymers.
  • NAD+ nicotinamide adenine dinucleotide
  • This is a key process for repairing DNA damage caused by DNA-damaging chemotherapeutics and radiation through base-excision repair (BER)-mediated single-strand break repair.
  • PARP inhibition thus causes death of cancer cells with defective DNA damage repair mechanisms.
  • olaparib marketed under the brand name Lynparza
  • Lynparza is used as a maintenance treatment for adult BRCA-mutated advanced ovarian cancer.
  • U.S. Patent No. 9,682,973 discloses PARP inhibitor compounds that have anticancer activity as PARP inhibitors.
  • PARP inhibitors There are other compounds known to be PARP inhibitors, but their effects on cancers with ATM and ASXL1 co-mutations are unknown.
  • Co-mutation refers to a state in which two or more genes or groups of genes have mutations at the same time. Since cancer often involves complex intertwining of mutations in various genes, the importance of co-mutation research is being emphasized.
  • the present inventors have discovered that a next-generation PARP inhibitor compound has an excellent therapeutic effect on cancers with ATM and ASXL1 co-mutations, and completed the present invention.
  • Patent Document 1 U.S. Patent No. 9,682,973
  • Patent Document 2 US Registered Patent No. 11325906
  • One aspect is to provide a pharmaceutical composition for the prevention or treatment of ATM and ASXL1 co-mutant cancer comprising a next-generation PARP inhibitor compound as an active ingredient.
  • Another aspect is to provide a method for preventing or treating ATM and ASXL1 co-mutant cancer, comprising the step of administering the pharmaceutical composition to a subject.
  • Another aspect is to provide a method of treating a cancer having ATM and ASXL1 co-mutations in a subject in need thereof, comprising administering a therapeutically effective amount of a next generation PARP inhibitor compound.
  • One aspect provides a pharmaceutical composition for the prevention or treatment of ATM and ASXL1 co-mutant cancer comprising a next-generation PARP inhibitor compound as an active ingredient.
  • Another aspect provides a method for preventing or treating ATM and ASXL1 co-mutant cancer comprising administering to a subject the pharmaceutical composition.
  • Another aspect provides a method of treating a cancer having ATM and ASXL1 co-mutations in a subject in need thereof, comprising administering a therapeutically effective amount of a next generation PARP inhibitor compound.
  • the PARP inhibitor compound is a compound of formula 1 (also referred to as '4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one') or a pharmaceutically acceptable salt thereof:
  • the PARP inhibitor compound is a compound of formula 2 (also referred to as '5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide') or a pharmaceutically acceptable salt thereof:
  • a composition comprising a next-generation PARP inhibitor compound, for example, a compound of formula 1, a compound of formula 2, or a pharmaceutically acceptable salt thereof, as an active ingredient has an excellent killing effect on cancer cells having ATM and ASXL1 co-mutations. In addition, it exhibits a long-term effect in ATM and ASXL1 co-mutation cancers. Therefore, a composition comprising a compound of formula 1, a compound of formula 2, or a pharmaceutically acceptable salt thereof as an active ingredient can be usefully utilized as a pharmaceutical composition for preventing or treating cancer having ATM and ASXL1 co-mutations.
  • a next-generation PARP inhibitor compound for example, a compound of formula 1, a compound of formula 2, or a pharmaceutically acceptable salt thereof
  • One aspect provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a poly(ADP ribose) polymerase (PARP) inhibitor compound selected from a compound of the following formula 1, a compound of the following formula 2, and pharmaceutically acceptable salts thereof for the prevention or treatment of ATM and ASXL1 co-mutated cancer.
  • PARP poly(ADP ribose) polymerase
  • the compound of the above chemical formula 1 is also referred to as 'Compound 1', '4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one', or Venadaparib.
  • the compound of the above chemical formula 2 is also referred to as 'Compound 2', '5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide', or Saruparib.
  • Compounds of chemical formula 1 (benadaparib) and chemical formula 2 (saruparib) are drugs expected to be next-generation PARP inhibitors and exhibit PARP1-selective inhibitory efficacy.
  • benadaparib and saruparib exhibit relatively high selective inhibitory efficacy against PARP1 compared to other PARP inhibitor drugs such as olaparib.
  • next-generation PARP inhibitor refers to a compound selected from a compound of formula 1, a compound of formula 2 below, and pharmaceutically acceptable salts thereof.
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof is readily available, for example, by the method described in U.S. Patent No. 9,682,973 or by preparing it in accordance therewith.
  • the compound of formula 2 or a pharmaceutically acceptable salt thereof is readily available, for example, by the method described in U.S. Patent No. 11,325,906 or by preparing it in accordance therewith.
  • the above documents are incorporated by reference in their entireties herein.
  • PARP poly(ADP ribose) polymerase
  • PARP-1 PARP-1
  • PARP-2 PARP-2
  • PARP-3 PARP-3
  • PARP inhibitor as used herein is an abbreviation for poly(ADP ribose) polymerase inhibitor, and includes PARP inhibitors known in the art and PARP inhibitors to be developed in the future.
  • PARP1 selective inhibitor refers to an inhibitor having selectivity for a capture effect for PARP1 over PARP2.
  • the PARP1 selective inhibitor can have a selectivity for a capture effect for PARP1 of about 50-fold or greater (e.g., about 60-fold or greater, about 70-fold or greater, about 80-fold or greater, about 90-fold or greater) over PARP2.
  • the PARP1 selective inhibitor can be benadaparib, saluparib, or a pharmaceutically acceptable salt thereof.
  • the PARP inhibitor is a PARP1 selective inhibitor.
  • co-mutation in this specification refers to the phenomenon in which multiple mutations occur in different genes in the same genome. That is, co-mutation is considered to be one of the key determinants of cancer, and a specific pair of co-mutations is thought to have a stronger prognostic predictive power than the individual components. It also refers to mutations that co-occur in different genes in the same individual.
  • the present inventors in a study to explore genetic alterations co-existing with HRR mutations to better predict the efficacy of monotherapy of a PARP inhibitor compound, which is a PARP inhibitor, in patients with metastatic pancreatic cancer, discovered that PARP inhibitors exhibit a durable response in cancers with ATM and ASXL1 co-mutation, thereby completing the present invention.
  • the compound of formula 1 (benadaparib), which is a PARP1 selective inhibitor, the compound of formula 2 (saruparib), or a pharmaceutically acceptable salt thereof, exhibits excellent effects in the prevention or treatment of ATM and ASXL1 co-mutated cancer.
  • the PARP inhibitor compound such as the compound of formula 1, the compound of formula 2, or a pharmaceutically acceptable salt thereof, can exhibit a durable response in cancers having ATM and ASXL1 co-mutations.
  • ASXL1 (Additional sex combs like transcriptional regulator 1) refers to a gene encoding a putative Polycomb group protein ASXL1.
  • ASXL1 gene information can be referenced from ASXL1 (ENSG00000171456) (NCBI identifier: 171023).
  • ASXL1 mutations are mainly observed in myelodysplastic syndrome, but are also observed in colorectal cancer and endometrial cancer.
  • ASXL1 is mutated in 4.42% of all cancers, including colon adenocarcinoma, lung adenocarcinoma, breast invasive ductal carcinoma, acute myeloid leukemia, and myelodysplastic syndrome, which have a high prevalence of mutations.
  • ATM ATM serine/threonine kinase
  • ATM gene information can be referenced to ATM (ENSG00000149311) (NCBI identifier: 472). This protein functions as a cell cycle checkpoint kinase and regulates several downstream effectors. Missense mutations, nonsense mutations, silent mutations, whole gene deletions, frameshift deletions and insertions, and in-frame deletions and insertions are observed in cancers such as endometrial cancer, colon cancer, and gastric cancer.
  • ATM is mutated in 5.58% of all cancers, including lung adenocarcinoma, colon adenocarcinoma, endometrial endometrioid adenocarcinoma, prostate adenocarcinoma, and breast invasive ductal carcinoma, which have a high prevalence of mutations.
  • ATM and ASXL1 co-mutation refers to mutations occurring in both the ATM gene and the ASXL1 gene.
  • ATM and ASXL1 co-mutation refers to a condition in which both ATM mutations and ASXL1 mutations occur in the same individual.
  • ATM mutation is also referred to by the abbreviation "ATMm”.
  • ASXL1 mutation is also referred to by the abbreviation "ASXL1m”.
  • ATMm and ASXL1m may be genetic mutations co-existing with HRR mutations in an individual.
  • the compound of formula 1, the compound of formula 2, or a pharmaceutically acceptable salt thereof, or a composition comprising them as an active ingredient not only exhibits PARP inhibitory activity as a PARP inhibitor and thus exhibits an effect on cancer, but also exhibits an excellent therapeutic effect in cancer having ATM and ASXL1 co-mutation.
  • the compound of formula 1, the compound of formula 2, or a pharmaceutically acceptable salt thereof, or a composition comprising them as an active ingredient exhibits a durable response in cancers having ATM and ASXL1 co-mutations.
  • the compound of formula 1, the compound of formula 2, or a pharmaceutically acceptable salt thereof, or a composition comprising them as an active ingredient can exhibit an antiproliferative effect in a concentration-dependent manner against a cell line associated with a cancer having ATM and ASXL1 co-mutations.
  • the compound of formula 1, the compound of formula 2, or a pharmaceutically acceptable salt thereof, or a composition comprising them as an active ingredient is expected to be widely applicable to cancers having ATM and ASXL1 co-mutations.
  • cancer includes various solid cancers.
  • solid cancer in this specification refers to a cancer that has characteristics distinct from blood cancer and is composed of a lump formed by abnormal cell growth in various solid organs such as the bladder, breast, intestine, kidney, lung, liver, brain, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin.
  • the cancer may be any one selected from pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, colon cancer, endometrial cancer, small cell lung cancer, neuroendocrine tumor, gallbladder cancer, biliary tract cancer, urothelial cancer, esophageal cancer, thyroid cancer, and blood cancer, but is not limited thereto.
  • the cancer may be pancreatic cancer.
  • the cancer may be colon cancer.
  • the compound of the above formula 1 or the compound of the formula 2 may also be included in the scope of the present invention in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt may be, for example, but is not limited to, an inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, etc.), an organic carboxylic acid (haloacetic acids such as acetic acid and trifluoroacetic acid, propionic acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, salicylic acid, etc.), an acidic sugar (glucuronic acid, galacturonic acid, gluconic acid, ascorbic acid, etc.), an acidic polysaccharide (hyaluronic acid, chondroitin sulfate, arginic acid, etc.), or a sulfonic acid such as chondroitin sulfate, an organic sulfonic acid including a sugar ester (me
  • the term “pharmaceutically acceptable” means that the composition exhibits the property of being non-toxic to cells or humans exposed to it.
  • a pharmaceutically acceptable salt of the compound of formula 1 or the compound of formula 2 can be prepared from the free base form of the compound of formula 1 or the compound of formula 2 by any suitable method known in the art.
  • it can be prepared by treating the free base with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.), an organic acid (e.g., acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid (e.g., glucuronic acid or galacturonic acid), an alpha hydroxyl acid (e.g., citric acid or tartaric acid), an amino acid (e.g., aspartic acid or glutamic acid), an aromatic acid (e.g., be
  • the pharmaceutical composition of the present invention may appropriately contain one or more pharmaceutically acceptable excipients within a range capable of achieving the effects of the present invention.
  • excipient refers to a pharmaceutically acceptable inactive ingredient used in the manufacture of a pharmaceutical preparation.
  • the excipient used in the present composition may be appropriately selected by referring to a literature known in the art, for example, the literature [Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press], which is incorporated herein by reference, and may be used without limitation as long as it is known in the art.
  • the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients selected from, but not limited to, diluents, binders, disintegrants, glidants, pH adjusting agents, isotonic agents, fluidizing agents, fillers, stabilizers, buffers, preservatives, analgesics, solubilizers, antioxidants, coating agents, and carriers.
  • pharmaceutically acceptable excipients selected from, but not limited to, diluents, binders, disintegrants, glidants, pH adjusting agents, isotonic agents, fluidizing agents, fillers, stabilizers, buffers, preservatives, analgesics, solubilizers, antioxidants, coating agents, and carriers.
  • the pharmaceutical composition of the present invention can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. Furthermore, it can be used in the form of external skin preparations such as ointments, lotions, sprays, patches, creams, powders, suspensions, gels, or gels.
  • Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the composition is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants and surfactants.
  • the pharmaceutical composition of the present invention can be formulated as an oral preparation, for example, a solid preparation for oral administration.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing the compound of the chemical formula 1, the compound of the chemical formula 2, or a pharmaceutically acceptable salt thereof with at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • excipients for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be included.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin.
  • Another aspect provides a method for preventing or treating ATM and ASXL1 co-mutant cancer, comprising administering the pharmaceutical composition to a subject.
  • the subject may be a non-human organism.
  • Another aspect provides a method of treating a cancer having ATM and ASXL1 co-mutations in a subject in need thereof, comprising administering a therapeutically effective amount of a PARP inhibitor compound selected from the group consisting of a compound of formula 1, a compound of formula 2, and pharmaceutically acceptable salts thereof.
  • a PARP inhibitor compound selected from the group consisting of a compound of formula 1, a compound of formula 2, and pharmaceutically acceptable salts thereof.
  • the method may further comprise a step of selecting a subject having ATM and ASXL1 co-mutations for the treatment of cancer.
  • the method may include measuring ATM and ASXL1 co-mutations in a biological sample obtained from a subject.
  • a sample can be collected from a subject, DNA extracted, PCR performed, DNA sequencing performed, and then mutation analysis performed to determine the presence of ATM and ASXL1 co-mutations.
  • methods for analyzing mutations in the ATM and ASXL1 genes can utilize techniques such as PCR, Sanger sequencing, and next-generation sequencing (NGS).
  • techniques such as PCR, Sanger sequencing, and next-generation sequencing (NGS).
  • biological sample means any biological sample collected from a subject. Biological samples include blood, plasma, serum, tumors, tissues, cells, etc.
  • prevention means any act of inhibiting or delaying the occurrence, spread, and recurrence of cancer by administering the pharmaceutical composition according to the present invention
  • treatment means any act of improving or beneficially changing the symptoms of a subject suspected of or diagnosed with cancer by administering the pharmaceutical composition.
  • Cancers that can be prevented or treated by the composition of the present invention include pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, colon cancer, endometrial cancer, small cell lung cancer, neuroendocrine tumors, gallbladder cancer, bile duct cancer, urothelial cancer, esophageal cancer, thyroid cancer, and blood cancer, and are preferably pancreatic cancer, but are not limited thereto.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount of the present invention means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level can be determined according to factors including the patient's health condition, the type and severity of cancer, the activity of the drug, the sensitivity to the drug, the administration method, the administration time, the administration route and the excretion rate, the treatment period, the drug used in combination or simultaneously, and other factors well known in the medical field.
  • the composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects by considering all of the above factors, and this can be easily determined by those skilled in the art.
  • the therapeutically effective amount of the compound of formula 1, the compound of formula 2, or a pharmaceutically acceptable salt thereof included in the composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally, the compound of formula 1 (Compound 1) or the compound of formula 2 (Compound 2) of the present invention may be administered in an amount of 0.1 to 1000 mg, preferably 1 to 500 mg, and more preferably 1 to 300 mg per day based on solid content, daily or every other day, intermittently, or administered once to three times a day in divided doses.
  • the dosage may be increased or decreased depending on the administration route, severity of the disease, sex, weight, age, and the like, and therefore the above dosage does not limit the scope of the present invention in any way.
  • a method of preventing or treating ATM and ASXL1 co-mutated cancer comprising administering to a subject in need thereof a compound of formula 1, a compound of formula 2, or a pharmaceutically acceptable salt thereof, or a composition comprising the same.
  • the method may further comprise the step of determining whether the subject has a co-mutation of ATM and ASXL1.
  • a co-mutation of ATM and ASXL1 can increase sensitivity to a compound of formula 1, a compound of formula 2, or a pharmaceutically acceptable salt thereof, or a composition comprising them as an active ingredient.
  • the step may be measuring the levels of an ATM mutation and an ASXL1 mutation occurring in the same individual.
  • subject or “individual” of the present invention means any animal, including a monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, which has developed or can develop cancer, and wherein the cancer can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the individual.
  • the individual may be an individual other than a human.
  • administration of the present invention means providing a predetermined substance to a patient by any appropriate method, and the route of administration of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. It may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, topically, intranasally, intrapulmonary, or rectally, but is not limited thereto.
  • the pharmaceutical composition of the present invention may be administered by any device through which the active substance can move to the target cell.
  • Preferred administration methods and formulations are intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip injection, etc.
  • the injection can be manufactured using aqueous solvents such as saline solution and Ringer's solution, non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., ethyl oleate, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.), and can contain pharmaceutical carriers such as stabilizers to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers to adjust pH, and preservatives to inhibit microbial growth (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).
  • aqueous solvents such as saline solution and Ringer's solution
  • non-aqueous solvents
  • the pharmaceutical composition of the present invention may be administered in combination with existing therapeutic agents.
  • the pharmaceutical composition of the present invention may further comprise a known anticancer agent in addition to the compound of formula 1, the compound of formula 2, or a pharmaceutically acceptable salt thereof as an active ingredient, and may be used in combination with other treatments known to treat these diseases.
  • Other treatments include, but are not limited to, chemotherapy, radiotherapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological treatments, immunotherapy, etc.
  • anticancer agents examples include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, and carboplatin; Oxaliplatin, 5-Fluorouracil (5-FU), gemcitabine, anti-cancer antibiotics such as dactinomycin (actinomycin D), doxorubicin (adriamycin), liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin C, and bleomycin; and plant alkaloids including, but not limited to, vincristine, vinblastine, vinorelbine, eribulin, paclitaxel, do
  • the present invention provides a pharmaceutical use of a compound of formula 1 ('4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one' or benadaparip) for use in the prevention or treatment of cancer having ATM and ASXL1 co-mutation.
  • the present invention provides a pharmaceutical use of a compound of formula 2 ('5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide' or saruparib) for use in the prevention or treatment of cancer having ATM and ASXL1 co-mutation.
  • composition according to one specific example may be directly applied to a method for preventing or treating cancer having ATM and ASXL1 co-mutations.
  • phase Ib/IIa basket trial (NCT04174716) evaluating compound 1 (benadaparib) monotherapy at doses of 80 mg, 120 mg, 160 mg, or 240 mg once daily.
  • This open-label, multicenter, phase Ib/IIa basket trial was conducted in patients with solid tumors and HRR mutations to evaluate the safety and efficacy of benadapalib in patients with HRR mutations. Additionally, the trial consisted of a Phase 1b benadapalib dose-selection study to determine the recommended Phase 2 dose (RP2D) and a Phase 2a non-randomized parallel dose expansion study to confirm the RP2D.
  • RP2D Phase 2 dose
  • Benadaparib was started at 80 mg and escalated to 120 mg, 160 mg, and 240 mg. Tumor response to treatment was assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST) (version 1.1) (RECIST 1.1). Exploratory blood samples were collected before the first dose to analyze genetic alterations other than HRR using ctDNA next-generation sequencing (NGS) (Guardant OMNI Gene Panel version 1.0, Redwood City, CA). The prevalence of co-mutations and mutual exclusivity between HRR and non-HRR mutations was statistically tested using The Cancer Genome Atlas (TCGA) Pan-cancer and AACR Project Genie version 13.0 registries. The efficacy between patients with co-mutations and those with only single mutations was presented.
  • NGS next-generation sequencing
  • ATM mutation ATM mutation, ATMm
  • ASXL1m ASXL1 mutation
  • PC pancreatic cancer
  • ORR overall response rate
  • PFS progression-free survival
  • the purpose of this study was to determine the anticancer effect of the test substance in ATM, ASXLI, and ATM-ASXLI mutants. To this end, isogenic cell lines were used to determine the difference in colony formation according to the test substance treatment.
  • Test substance 1 Venadaparib (compound of chemical formula 1)
  • the above cell lines were selected as cell lines used to evaluate the biomarker-selective anticancer effects of PARP inhibitors.
  • DLD-1 DLD-1 ATM - / - , DLD-1 ASXL1 - / - and DLD-1 ATM-ASXL1 - / - cells.
  • RPMI1640 medial supplemented with 10% FBS and 1% penicillin streptomycin is used.
  • the cell culture environment is 37°C, 95% air, 5% CO2 .
  • the cultured DLD-1, DLD-1 ATM - / - , DLD-1 ASXL1 - / - and DLD-1 ATM-ASXL1 - / - cells are refeeded 2-3 times a week, washed with PBS, and attached cells are detached with 0.25% (w/v) Trypsin-EDTA solution (Invitrogen TM ).
  • the detached cells are centrifuged (5 minutes, 125 X 9), and the medium is added to the collected cells, and the cells are mixed well with a pipette so that the cells are evenly dispersed and used in the experiment while subculturing.
  • DLD1 is a human colon adenocarcinoma cell line.
  • the ECACC documents a pseudodiploid karyotype.
  • Chromosome 11 108,223,044-108,369,102 forward strand
  • Target transcript ATM-229 ENST00000675843.1 3056aa CCDS31669
  • Chromosome 20 32,358,330-32,439,319 forward strand
  • Target transcript ASXL-202 ENST00000375687.10 1541aa CCDS13201
  • DLD-1, DLD-1 ATM - / - , DLD-1 ASXL1 - / - , and DLD-1 ATM-ASXL1 - / - cells are prepared at a concentration of 2.5 X 10 2 cells/well using the respective culture media. After that, the cells are stabilized in a cell incubator at 37°C and 5% CO 2 for 14 hours. After the stabilization step, the cells are treated with each test substance at the concentration described in 2.4 Test group composition, and then cultured in a cell incubator at 37°C and 5% CO 2 for 7 days.
  • test substance is treated once during the test period, and cultured for 7 days after test substance treatment.
  • DLD-1, DLD-1 ATM - / - , DLD-1 ASXL1 - / - and DLD-1 ATM-ASXL1 - / - cells cultured in a 75T flask were prepared at a concentration of 2.5 X 10 2 cells/well using each culture medium. After a 14-hour cell stabilization step, the test substance was added to the cells at the concentration indicated in 2.4 Test group composition. After culturing for 7 days, the inhibition of tumor cell colony formation by the test substance treatment was confirmed.
  • the experimental method is as follows.
  • DLD-1, DLD-1 ATM - / - , DLD-1 ASXL1 - / - and DLD-1 ATM-ASXL1 - / - cells were seeded at a density of 2.5 X 10 2 cells/well using the respective culture media, and then stabilized in a 5% CO 2 cell incubator at 37°C for 14 hours.
  • Test substance dilution ratio DLD-1, DLD-1 ASXL1 - / - : 40,000 nM ⁇ 2.56 nM
  • the results of this test are analyzed using parametric multiple comparison procedures. Normality of data is assumed, and one-way ANOVA is used for the test. If the results are significant, Dunnett's multiple comparison test is used for the post-test to analyze the significant differences between the test groups.
  • IC 50 analysis was performed using Prism 7.04 (GraphPad Software Inc., San Diego CA, USA).
  • Table 3 summarizes the colony formation analysis results (Pixel: 4 ⁇ 5 ⁇ ) in each test substance treatment group and shows the results expressed as a multiple of mutation/wild. The smaller the value is than 1, the higher the sensitivity to the drug.
  • test substances were evaluated using in vitro enzymatic assays.
  • test substance solution The stock concentration, dissolution solvent, test range, and intermediate dilution of each test substance solution are as follows.
  • Fluorescence polarization was analyzed with Tecan Magellan 6 software, with the wells containing DNA used as reference. Fluorescence polarization data were then evaluated using the software Graphpad Prism. The ED 50 values of the evaluated test substances are summarized in the table below.
  • Venadaparib and Saruparib are next-generation PARP inhibitors that show higher selectivity for PARP1 over PARP2 than other PARP inhibitors.

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Abstract

La présente invention concerne l'utilisation, en tant qu'agent anticancéreux, d'un inhibiteur de PARP de nouvelle génération et, plus spécifiquement, une composition pharmaceutique comprenant, en tant que principe actif, un inhibiteur de PARP de nouvelle génération pour le traitement du cancer ayant une co-mutation ATM et ASXL1.
PCT/KR2024/005536 2023-04-25 2024-04-24 Utilisation, en tant qu'agent anticancéreux, d'inhibiteur de parp de nouvelle génération pour le traitement du cancer ayant une co-mutation atm et asxl1 Pending WO2024225750A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210137162A (ko) * 2019-03-12 2021-11-17 아르커스 바이오사이언시즈 인코포레이티드 종양유전자-유발 암의 치료
KR20220125183A (ko) * 2021-03-04 2022-09-14 아이디언스 주식회사 Parp 억제제에 내성을 가진 환자군의 암 치료제로서의 프탈라지논 유도체의 항암제 용도
WO2022226655A1 (fr) * 2021-04-28 2022-11-03 Repare Therapeutics Inc. Méthodes de traitement des cancers comportant une mutation biallélique de perte de fonction ou de surexpression génique
WO2022254256A1 (fr) * 2021-06-02 2022-12-08 Idience Co., Ltd. Méthodes de traitement de troubles avec des dérivés de phtalazinone
WO2022261777A1 (fr) * 2021-06-16 2022-12-22 Repare Therapeutics Inc. Utilisation d'inhibiteurs d'atr en association avec des inhibiteurs de parp pour le traitement du cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210137162A (ko) * 2019-03-12 2021-11-17 아르커스 바이오사이언시즈 인코포레이티드 종양유전자-유발 암의 치료
KR20220125183A (ko) * 2021-03-04 2022-09-14 아이디언스 주식회사 Parp 억제제에 내성을 가진 환자군의 암 치료제로서의 프탈라지논 유도체의 항암제 용도
WO2022226655A1 (fr) * 2021-04-28 2022-11-03 Repare Therapeutics Inc. Méthodes de traitement des cancers comportant une mutation biallélique de perte de fonction ou de surexpression génique
WO2022254256A1 (fr) * 2021-06-02 2022-12-08 Idience Co., Ltd. Méthodes de traitement de troubles avec des dérivés de phtalazinone
WO2022261777A1 (fr) * 2021-06-16 2022-12-22 Repare Therapeutics Inc. Utilisation d'inhibiteurs d'atr en association avec des inhibiteurs de parp pour le traitement du cancer

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