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WO2025034640A1 - Méthodes et compositions pour le traitement de tumeurs malignes de la gaine nerveuse périphérique - Google Patents

Méthodes et compositions pour le traitement de tumeurs malignes de la gaine nerveuse périphérique Download PDF

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Publication number
WO2025034640A1
WO2025034640A1 PCT/US2024/040932 US2024040932W WO2025034640A1 WO 2025034640 A1 WO2025034640 A1 WO 2025034640A1 US 2024040932 W US2024040932 W US 2024040932W WO 2025034640 A1 WO2025034640 A1 WO 2025034640A1
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Prior art keywords
prmt5
disclosure
methods
inhibitor
peripheral nerve
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PCT/US2024/040932
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English (en)
Inventor
Peter Olson
Lars Daniel ENGSTROM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mirati Therapeutics Inc
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Mirati Therapeutics Inc
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Publication of WO2025034640A1 publication Critical patent/WO2025034640A1/fr
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Classifications

    • 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

  • This disclosure relates to methods of treating cancer.
  • This disclosure further relates to treating cancer in a subject with compounds that are inhibitors of protein arginine N-methyl transferase 5 (PRMT5). More particularly, this disclosure relates to treatment of malignant peripheral nerve sheath tumors (MPNST).
  • PRMT5 protein arginine N-methyl transferase 5
  • MPNST malignant peripheral nerve sheath tumors
  • PRMT5 is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to an omega-nitrogen of the guanidino function of protein L-arginine residues (omega-monomethylation) and the transfer of a second methyl group to the other omega-nitrogen, yielding symmetric dimethylarginine (sDMA).
  • SAM S-adenosyl-L-methionine
  • sDMA symmetric dimethylarginine
  • PRMT5 forms a complex with methylosome protein 50 (MEP50), which is required for substrate recognition and orientation and is also required for PRMT5-catalyzed histone 2A and histone 4 methyltransferase activity (e.g., see Ho et al. (2013) PLoS ONE 8(2): e57008).
  • MTAP methylthioadenosine phosphorylase
  • MTA methylthioadenosine
  • PRMT5 methylthioadenosine
  • Inhibition of PRMT5 activity results in reduced methylation activity and increased sensitivity of cellular proliferation to PRMT5 depletion or loss of activity.
  • the loss of MTAP activity reduces methylation activity of PRMT5 making the cells selectively dependent on PRMT5 activity.
  • Malignant peripheral nerve sheath tumors are a form of cancer of the connective tissue or sheath that surrounds and protects peripheral nerves. Malignant peripheral nerve sheath tumors were previously named neurofibrosarcomas.
  • Malignant peripheral nerve sheath tumors grow in any of the soft tissues of the body, such as muscle, fat, tendons, ligaments, lymph and blood vessels, nerves, and other tissue that connects and supports the body.
  • MPNST grows quickly and can spread to other parts of the body.
  • One aspect of the disclosure provides methods for treating malignant peripheral nerve sheath tumors (MPNST) in a subject. Such methods include administering to the subject a therapeutically effective amount of a PRMT5 inhibitor.
  • the disclosure provides methods for reducing the size of malignant peripheral nerve sheath tumors (MPNST) in a subject. Such methods include administering to the subject a therapeutically effective amount of a PRMT5 inhibitor.
  • the methods and compositions described herein can be configured by the person of ordinary skill in the art to meet the desired need.
  • the present disclosure provides improvements in treating cancer in a subject.
  • the terms “subject” or “patient” are used interchangeably, refers to any animal, including mammals, and most preferably humans.
  • the methods provided herein may be used for the treatment of a wide variety of cancer including tumors, including malignant peripheral nerve sheath tumors (MPNST).
  • the methods involve administration of a PRMT5 inhibitor to a patient or subject in need of such treatment.
  • a “PRMT5 inhibitor” as used herein refers to compounds of the disclosure as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of PRMT5, particularly, in the presence of bound MTA in vitro or in vivo or in cells in the presence of elevated levels of MTA.
  • the PRMT5 inhibitor is an MTA-cooperative PRMT5 inhibitor.
  • the PRMT5 inhibitor of the disclosure is any one of the PRMT5 inhibitors disclosed in published International Patent Application No. WO 2021/050915 A1, published 18 March 2021, which is incorporated by reference in its entirety.
  • the PRMT5 inhibitor of the disclosure is any one of the PRMT5 inhibitors disclosed in published International Patent Application No.
  • the PRMT5 inhibitor in the methods of the disclosure as described herein is a compound having formula (IA), (IB), (IC) or (ID)
  • the PRMT5 inhibitor is a compound of the formula: or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is a compound of the formula: or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is a pharmaceutically acceptable salt of a compound of the formula:
  • the PRMT5 inhibitor is a compound of the formula:
  • PRMT5 inhibitor is: [0025] In certain embodiments of the methods of the disclosure as described herein, the
  • PRMT5 inhibitor is:
  • the PRMT5 inhibitor of the disclosure may be synthesized according to procedures set forth in published International Patent Application No. WO 2021/050915, or published International Patent Application No. WO/2022/192745.
  • the PRMT5 inhibitor of the disclosure may be provided as a pharmaceutical composition comprising a therapeutically effective amount of such inhibitor and a pharmaceutically acceptable carrier, excipient, and/or diluents.
  • the PRMT5 inhibitor of the disclosure may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • the PRMT5 inhibitor of the disclosure are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.
  • compositions of the disclosure may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • diluents such as a cell, cell culture, tissue, or organism
  • solubilizers such as a cell, cell culture, tissue, or organism
  • the preparation of pharmaceutically acceptable formulations is described in, e.g., Remington’s Pharmaceutical Sciences, 18 th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
  • the PRMT5 inhibitor of the disclosure are administered in a therapeutically effective amount.
  • therapeutically effective amount or “effective amount” refers to the amount of active agent that elicits the biological or medicinal response that is being sought in a tissue, system, subject or human by a researcher, medical doctor or other clinician. In general, the therapeutically effective amount is sufficient to deliver the biological or medicinal response to the subject without causing serious toxic effects.
  • a dose of the active agent may be in the range from about 0.01 to 300 mg/kg per day, such as 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg/kg body weight of the recipient per day.
  • a typical topical dosage will range from 0.01 to 3% wt/wt in a suitable carrier.
  • the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.01 to 300 mg/kg per day.
  • the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.1 to 100 mg/kg per day, or 25 to 100 mg/kg per day, or 50 to 100 mg/kg per day.
  • the therapeutically effective amount of the PRMT5 inhibitor is less than 1% of, e.g., less than 10%, or less than 25%, or less than 50% of the clinically- established therapeutic amount (e.g., such as the amount required when the PRMT5 inhibitor is administered by itself).
  • the PRMT5 inhibitor may also be administered in combination with another anticancer compound or therapy.
  • Combination therapy is intended to embrace administration of each agent in a sequential manner, a substantially simultaneous manner or in a single dosage form.
  • Each combination therapy is administered in a regimen that will provide beneficial effects of the drug combination.
  • Each compound of the combination therapy can be formulated as a separate composition such that separate compositions are given sequentially or in a substantially simultaneous manner, such as in a single dosage form having a fixed ratio of the active agents or in multiple or a separate dosage forms for each agent.
  • the disclosure is not limited in the sequence of administration: the PRMT5 inhibitor of the disclosure may be administered either prior to or after (i.e., sequentially), or at the same time (i.e., simultaneously) as administration of an additional anti-cancer compound.
  • the methods of disclosure are useful as a first-line treatment.
  • the subject has not previously received another first-line of therapy.
  • the methods of disclosure are also useful as a first-line maintenance or a second-line treatment.
  • the subject has previously completed another first-line of therapy.
  • the methods of the disclosure may provide a delay in progression and relapse of cancer in subjects that have previously completed another first-line chemotherapy.
  • the subject has previously completed a platinum- and/or taxane-based chemotherapy (e.g., carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, and the like).
  • the subject has previously completed another first-line chemotherapy and is in partial response to such chemotherapy.
  • Example 1 In Vitro Proliferation Assay
  • Viability assays were performed using the MTAP deleted human MPNST (Malignant Peripheral Nerve Sheath Tumor) cell lines HS-PSS and SNF96.2.
  • MPNST Malignant Peripheral Nerve Sheath Tumor
  • an optimized cell number for each cell line was plated in 96-well plates and incubated overnight at 37C plus 5% CO2.
  • the following day baseline CTG (CellTiter-Glo; Promega cat. No. G7573) readings were collected from designated wells and assay plates were treated with DMSO (as the control) or a dose response of MRTX1719.
  • the cells were then incubated at 37°C plus 5% CO2 for five days. After this duration of treatment, CTG readings were collected.
  • the MRTX1719 relative viability IC50 values for each cell line were calculated using the end of treatment CTG values after Day 0 baseline subtraction for each cell line using GraphPad PRISM software. The results of these assays are shown in FIG. 1A and 1 B and the IC50 for each cell line is shown in Table 1.
  • Example 2 In Vivo Tumor Growth Inhibition Study
  • mice Immunocompromised nude/nude mice were inoculated in the hind flank with patient derived tumor samples harboring an MTAP deletion. When mean tumor volumes reached ⁇ 90 mm 3 in size, the mice were divided into two groups of 5 mice each. The first group was administered vehicle only (0.5% Methylcellulose (4000cps) + 0.2% TWEEN80 in water). The second group was administered a single agent dose of MRTX1719 at the indicated dose for the indicated treatment duration. The dosing used is reported in Table 2.
  • the tumor volumes were measured over 28 days on study, and the average tumor volumes (mm 3 ) of each treatment group are shown in Table 2.
  • MRTX1719 treatment for 28 days resulted in 97% TGI.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des méthodes de traitement du cancer. La présente divulgation concerne en outre le traitement du cancer chez un sujet avec des composés qui sont des inhibiteurs de la protéine arginine N-méthyltransférase 5 (PRMT5). Plus particulièrement, la présente divulgation concerne le traitement de tumeurs malignes de la gaine nerveuse périphérique (MPNST).
PCT/US2024/040932 2023-08-08 2024-08-05 Méthodes et compositions pour le traitement de tumeurs malignes de la gaine nerveuse périphérique Pending WO2025034640A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363518312P 2023-08-08 2023-08-08
US63/518,312 2023-08-08
US202363588563P 2023-10-06 2023-10-06
US63/588,563 2023-10-06

Publications (1)

Publication Number Publication Date
WO2025034640A1 true WO2025034640A1 (fr) 2025-02-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448388B2 (en) 2023-04-21 2025-10-21 Gilead Sciences, Inc. PRMT5 inhibitors and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016145150A2 (fr) * 2015-03-11 2016-09-15 The Broad Institute Inc. Traitement sélectif de cancer dépendant de prmt5
WO2021050915A1 (fr) 2019-09-12 2021-03-18 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 à coopération avec la mta
WO2022192745A1 (fr) 2021-03-11 2022-09-15 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 coopératif à base de mta
WO2022256806A1 (fr) * 2021-06-02 2022-12-08 Ideaya Biosciences, Inc. Polythérapie comprenant un inhibiteur de mat2a et un inhibiteur de prmt de type ii
WO2024049948A1 (fr) * 2022-09-01 2024-03-07 Mirati Therapeutics, Inc. Polythérapies à l'aide d'inhibiteurs de prmt5 et d'inhibiteurs de la famille bcl-2 pour le traitement du cancer
WO2024170488A1 (fr) * 2023-02-13 2024-08-22 Astrazeneca Ab Inhibiteur de prmt5 destiné à être utilisé en thérapie anticancéreuse

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016145150A2 (fr) * 2015-03-11 2016-09-15 The Broad Institute Inc. Traitement sélectif de cancer dépendant de prmt5
WO2021050915A1 (fr) 2019-09-12 2021-03-18 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 à coopération avec la mta
WO2022192745A1 (fr) 2021-03-11 2022-09-15 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 coopératif à base de mta
WO2022256806A1 (fr) * 2021-06-02 2022-12-08 Ideaya Biosciences, Inc. Polythérapie comprenant un inhibiteur de mat2a et un inhibiteur de prmt de type ii
WO2024049948A1 (fr) * 2022-09-01 2024-03-07 Mirati Therapeutics, Inc. Polythérapies à l'aide d'inhibiteurs de prmt5 et d'inhibiteurs de la famille bcl-2 pour le traitement du cancer
WO2024170488A1 (fr) * 2023-02-13 2024-08-22 Astrazeneca Ab Inhibiteur de prmt5 destiné à être utilisé en thérapie anticancéreuse

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ANONYMOUS CHRISTOPHER R. ET AL: "Abstract P165: MRTX1719: A first-in-class MTA-cooperative PRMT5 inhibitor that selectively elicits antitumor activity in MTAP/CDKN2A deleted cancer models | Molecular Cancer Therapeutics | American Association for Cancer Research", MOLECULAR CANCER THERAPEUTICS, vol. 20, no. 12_Supplement, 1 December 2021 (2021-12-01), US, pages P165 - P165, XP093213056, ISSN: 1535-7163, Retrieved from the Internet <URL:https://aacrjournals.org/mct/article/20/12_Supplement/P165/675974/Abstract-P165-MRTX1719-A-first-in-class-MTA> DOI: 10.1158/1535-7163.TARG-21-P165 *
ANONYMOUS LAURA ET AL: "Abstract 3319: The MTA-cooperative PRMT5 inhibitor, MRTX1719, demonstrates increased anti-tumor activity in combination with KRAS mutant-selective inhibitors in MTAP del,KRAS-mutant cancers | Cancer Research | American Association for Cancer Research", CANCER RESEARCH, vol. 84, no. 6_Supplement, 22 March 2024 (2024-03-22), US, pages 3319 - 3319, XP093213057, ISSN: 1538-7445, Retrieved from the Internet <URL:https://aacrjournals.org/cancerres/article/84/6_Supplement/3319/739108/Abstract-3319-The-MTA-cooperative-PRMT5-inhibitor> DOI: 10.1158/1538-7445.AM2024-3319 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448388B2 (en) 2023-04-21 2025-10-21 Gilead Sciences, Inc. PRMT5 inhibitors and uses thereof

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