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WO2025208233A1 - Inhibiteur de parp/hdac double pour le traitement du cancer du sein, du cancer de l'ovaire et du cancer de la prostate - Google Patents

Inhibiteur de parp/hdac double pour le traitement du cancer du sein, du cancer de l'ovaire et du cancer de la prostate

Info

Publication number
WO2025208233A1
WO2025208233A1 PCT/CA2025/050498 CA2025050498W WO2025208233A1 WO 2025208233 A1 WO2025208233 A1 WO 2025208233A1 CA 2025050498 W CA2025050498 W CA 2025050498W WO 2025208233 A1 WO2025208233 A1 WO 2025208233A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
compound
cancer
acceptable salt
hydroxyacrylamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CA2025/050498
Other languages
English (en)
Inventor
Mads DAUGAARD
Dennis M. Brown
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.)
Rakovina Therapeutics Inc
Original Assignee
Rakovina Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rakovina Therapeutics Inc filed Critical Rakovina Therapeutics Inc
Publication of WO2025208233A1 publication Critical patent/WO2025208233A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • PARP Poly-(ADP-ribose)-polymerase (PARP) proteins catalyze PARylation of cellular proteins using an ADP (adenosine diphosphate)-ribose subunit of nicotinamide adenine dinucleotide (NAD+) as the donor.
  • ADP adenosine diphosphate
  • NAD+ nicotinamide adenine dinucleotide
  • the human genome encodes 17 PARP enzymes where at least PARP 1-3 has critical functions in DNA repair, PARP1 being the best characterized.
  • PARP1 is essential for the repair of single-strand DNA breaks (SSBs), which is the most common type of breakpoint lesion in cellular DNA.
  • SSBs single-strand DNA breaks
  • PARP1 When cells encounter SSBs, PARP1 binds the lesion and initiates a PARylation cascade of itself and histones embedded in the chromatin surrounding the SSB lesion. This PARylation event serves as a signal to recruit the SSB repair machinery to patch the lesions before and during DNA replication in the S-phase of the cell cycle. Efficient SSB repair is important to prevent replication stress and the more severe double-strand break (DSB) lesions that occur in S-phase when unrepaired SSB lesions collide with the replication forks. DSB lesions in S-phase are mainly repaired by homologous recombination (HR) that relies on proteins such as BRCA1 and BRCA2.
  • HR homologous recombination
  • Deleterious mutations in BRCA1/2 are found in subsets of breast, ovarian, and prostate tumors, and sporadically in other solid tumor indications. These HR-deficient tumors are indirectly dependent on proficient PARP enzyme activity to avoid accumulation of catastrophic DSBs in S-phase and initiation of cell death. This dependency has paved the way for PARP inhibition as a therapeutic strategy to create synthetic lethality in tumor cells with BRCAl/2-deficiencies.
  • the disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and Compound A, or a pharmaceutically acceptable salt thereof, for treating breast cancer, ovarian cancer, or prostate cancer in a subject.
  • the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and Compound A, or a pharmaceutically acceptable salt thereof, for treating breast cancer in a subject.
  • the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and Compound A, or a pharmaceutically acceptable salt thereof, for treating ovarian cancer in a subject.
  • the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and Compound A, or a pharmaceutically acceptable salt thereof, for treating prostate cancer in a subject.
  • FIG. 1 is a schematic illustration of a proposed mechanism of action of dual PARP/HDAC inhibitor compounds (kt-3OOO compounds).
  • FIG. 6B compares cell viability for breast cancer cell line MDA-MB-231 (BRCA- proficient) treated with Compound A and olaparib.
  • the administration of Compound A, or a pharmaceutically acceptable salt thereof can be a systemic administration, a local administration, or a topical administration.
  • subject or “patient” is intended to include mammalian organisms.
  • subjects or patients include humans and non-human mammals, e.g., nonhuman primates, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human.
  • Cells were plated on a 96-well plate (1000-5000 cells per well) in 100 pL appropriate medium and allowed to attach overnight. 100 pL medium containing DMSO or increasing concentration of test compound was added to each well. Cells were maintained at 37°C with 5% CO2 and 95% humidity for ten days for CHLA10, SUM149PT, MDA-MB-231, UWB1.289, UWB1.289+BRCA1, LNCaP and PC3, and three days for TC32 and A673.
  • Cell-Titer-Glo® viability assay was carried out for ten-day assays.150 pL media per well was removed and plates were equilibrated at RT for 30 min, then CellTiter-Glo® assay reagent was added to the wells. The plates were gently shaken on an orbital shaker for 2 min and incubated at RT for 10 min in the dark. Luminescence was measured using a Tecan Infinite M200Pro microplate reader. All measurements were carried out in triplicate. For TC32 and A673, the plates were imaged on an Incucyte® S3 live cell imaging system after the treatments and % confluency was measured using the Incucyte® software.
  • ECso values were calculated using a four-parameter variable slope non-linear regression in GraphPad Prism 8 (GraphPad Software Inc.). The mean ECso value ⁇ SD was calculated using three biological replicates.
  • Results for breast cancer cell lines are shown in FIGS. 6A and 6B.
  • Results for ovarian cancer cell lines are shown in FIGS. 7A and 7B.
  • Results for prostate cancer cell lines are shown in FIGS. 8 A and 8B.

Landscapes

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

Abstract

L'invention concerne une méthode de traitement du cancer du sein, du cancer de l'ovaire ou du cancer de la prostate chez un sujet, comprenant l'administration à un sujet dont l'état le nécessite d'une quantité thérapeutiquement efficace de (E)-3-(2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophtalazin-1-yl)méthyl)benzoyl)pipérazin-1-yl)pyrimidin-5-yl)-N-hydroxyacrylamide, ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/CA2025/050498 2024-04-05 2025-04-04 Inhibiteur de parp/hdac double pour le traitement du cancer du sein, du cancer de l'ovaire et du cancer de la prostate Pending WO2025208233A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463575232P 2024-04-05 2024-04-05
US63/575,232 2024-04-05

Publications (1)

Publication Number Publication Date
WO2025208233A1 true WO2025208233A1 (fr) 2025-10-09

Family

ID=97265745

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2025/050498 Pending WO2025208233A1 (fr) 2024-04-05 2025-04-04 Inhibiteur de parp/hdac double pour le traitement du cancer du sein, du cancer de l'ovaire et du cancer de la prostate

Country Status (1)

Country Link
WO (1) WO2025208233A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898378A (zh) * 2012-11-16 2013-01-30 江苏先声药业有限公司 一类酞嗪酮衍生物及其应用
WO2024092354A1 (fr) * 2022-11-04 2024-05-10 Rakovina Therapeutics, Inc. Inhibiteur de parp-hdac bispécifique pour le traitement du sarcome d'ewing

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898378A (zh) * 2012-11-16 2013-01-30 江苏先声药业有限公司 一类酞嗪酮衍生物及其应用
WO2024092354A1 (fr) * 2022-11-04 2024-05-10 Rakovina Therapeutics, Inc. Inhibiteur de parp-hdac bispécifique pour le traitement du sarcome d'ewing

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YUAN, ZIGAO ET AL.: "Olaparib Hydroxamic Acid Derivatives as Dual PARP and HDAC Inhibitors for Cancer Therapy", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 25, 31 May 2017 (2017-05-31), pages 4100 - 4109, XP085114610, DOI: 10.1016/j.bmc.2017.05.058 *

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