WO2023114867A2 - Therapeutic targeting of gastrointestinal stromal tumor (gist) by disrupting the menin-mll epigenetic complex - Google Patents

Therapeutic targeting of gastrointestinal stromal tumor (gist) by disrupting the menin-mll epigenetic complex Download PDF

Info

Publication number
WO2023114867A2
WO2023114867A2 PCT/US2022/081587 US2022081587W WO2023114867A2 WO 2023114867 A2 WO2023114867 A2 WO 2023114867A2 US 2022081587 W US2022081587 W US 2022081587W WO 2023114867 A2 WO2023114867 A2 WO 2023114867A2
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
menin
gist
moz
tki
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.)
Ceased
Application number
PCT/US2022/081587
Other languages
English (en)
French (fr)
Other versions
WO2023114867A3 (en
Inventor
Scott A. Armstrong
Matthew L. HEMMING
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.)
Dana Farber Cancer Institute Inc
Original Assignee
Dana Farber Cancer Institute 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 Dana Farber Cancer Institute Inc filed Critical Dana Farber Cancer Institute Inc
Priority to AU2022410890A priority Critical patent/AU2022410890A1/en
Priority to MX2024007201A priority patent/MX2024007201A/es
Priority to KR1020247016183A priority patent/KR20240121720A/ko
Priority to US18/717,194 priority patent/US20250041299A1/en
Priority to EP22908673.1A priority patent/EP4447972A4/en
Priority to IL311862A priority patent/IL311862A/en
Priority to CA3235383A priority patent/CA3235383A1/en
Priority to CN202280073517.6A priority patent/CN118234497A/zh
Priority to JP2024533005A priority patent/JP2025503385A/ja
Publication of WO2023114867A2 publication Critical patent/WO2023114867A2/en
Publication of WO2023114867A3 publication Critical patent/WO2023114867A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • 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
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • FIGs. 3A-3I are a series of heat maps, Venn diagrams, scatter plots, and tracks that show the genomic localization of MOZ and Menin-MLL complexes in GIST.
  • FIG. 3A is a series of heat maps demonstrating genomic localization in GIST-T1 of H3K27ac, H3K9ac, H3K4me3, BRPF1, and KAT6A by ChlP-seq, and Menin and MLLln by CUT&Tag.
  • FIGs. 3B-3D are diagrams showing the overlap of MACS-defined peaks.
  • FIG. 3B is a diagram depicting BRPF1 and KAT6A.
  • FIG. 3C is a diagram depicting Menin and BRPF1.
  • FIG. 4C is a bar plot showing a day 21 cell count normalized to DMSO following treatment of GIST48B, GIST-T1 or KIT enhancer independent cell line GIST-Tl/KIT Ae11 (endogenous KIT knocked out with rescue of CMV promoter driven mutant KIT) with VTP- 50469 with or without WM-1119.
  • FIG. 4D a bar plot showing a growth over time assay in GIST430, with relative cell count shown at day 42 following treatment with VTP-50469 at 0.5 pM with or without VTP-50469; the combination was used with each drug at 0.1 pM.
  • FIGs. 5A-5W are a series of scatter and bar plots showing the transcriptional effects of Menin inhibition with and without MOZ inhibition.
  • FIG. 5A is a scatter plot showing the ratio of expression between inhibitor and DMSO treatment for all expressed genes following 5 days of inhibitor treatment in GIST-T1 cells.
  • FIG. 5B is a butterfly plot of all Hallmark gene sets indicating the NES and FDR q-value comparing VTP-50469 (blue) at day 5 to DMSO control.
  • FIG. 5C is a scatter plot showing the Hallmark MTORC1 Signaling and EMT gene sets comparing DMSO and VTP-50469.
  • FIG. 5A-5W are a series of scatter and bar plots showing the transcriptional effects of Menin inhibition with and without MOZ inhibition.
  • FIG. 5A is a scatter plot showing the ratio of expression between inhibitor and DMSO treatment for all expressed genes following 5 days of inhibitor treatment in GIST-T1 cells.
  • FIG. 5B is a butterfly plot of all Hallmark gene sets indicating
  • FIGs. 12A-12C are a series of scatter and bar plots that illustrate the transcriptional effects of Menin inhibition.
  • FIG. 12A is a scatter plot showing the ratio of expression between inhibitor and DMSO treatment for the top 500 essential genes following 5 days of inhibitor treatment.
  • FIG. 12B is a bar plot showing the relative expression of negative regulators of KIT signaling SPRY2, SPRY4 and DUSP6 upon 1- or 5-day treatment with VTP-50469.
  • FIG. 12C is a bar plot showing the relative expression of KIT upon 1- or 5-day treatment with VTP- 50469.
  • FIG. 14A-14F are line plots and a series of photomicrographs that show the effects of Menin inhibition in vivo.
  • FIG. 14A is a line plot showing the weight of mice engrafted with the GIST-T1 cell line and treated for 28 days with imatinib, VTP-50469, a combination of imatinib and VTP-50469, and a vehicle control.
  • FIG. 14A is a line plot showing the weight of mice engrafted with the GIST-T1 cell line and treated for 28 days with imatinib, VTP-50469, a combination of imatinib and VTP-50469, and a vehicle control.
  • Menin inhibitors that may be useful in the practice of the present disclosure are known in the art. See, e.g, WO 2017/112768, WO 2017/214367, WO 2018/053267, WO 2020/069027 Al, WO 2021/207335 Al, U.S. 2021/0115018 Al, U.S. 2019/0307750, U.S. 20160339035 (compounds of formula (I) therein), and Borkin et al., Cancer Cell 27(4):5 9- 602 (2015).
  • the daily dosage of the TKI imatinib is about 100 mg/day.
  • the KIT inhibitor is administered in a daily dosage of about 300 mg/day, about 340 mg/day, about 400 mg/day, about 600 mg/day, or about 800 mg/day.
  • the methods may entail administration of a Menin inhibitor, and optionally one or more additional active agents or pharmaceutical compositions thereof to the patient in a single dose or in multiple doses (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses).
  • the frequency of administration may range from once a day up to about once every eight weeks. In some embodiments, the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments entails a 28-day cycle which includes daily administration for 3 weeks (21 days) followed by a 7-day “off’ period, or administration for 4 weeks followed by a 14-day “off’ period.
  • kits or pharmaceutical systems may include one or more dosage formulations containing a Menin inhibitor and a pharmaceutically acceptable carrier disposed in a suitable container, e.g., tube, vial, ampoule, bottle, syringe, or bag.
  • the kit or pharmaceutical system may also include one or more dosage formulations of a TKI.
  • the kit or pharmaceutical system may also include one or more dosage formulations of a MOZ inhibitor.
  • the kit or pharmaceutical system may also include one or more dosage formulations of a TKI inhibitor and one or more dosage formulations of a MOZ inhibitor.
  • the additional actives may be formulated separately or together, and may be disposed in the same or separate containers
  • the kits or pharmaceutical systems of the disclosure may also comprise printed instructions for using the additional active(s) contained therein.
  • a third PCR reaction was performed to enrich for full-length amplicons (primers are detailed in Table 1 - Table 3).
  • Final amplicon libraries were purified by agarose gel electrophoresis and extraction with a QIAquick Gel Extraction Kit (Qiagen Cat# 28704).
  • Next generation sequencing was performed on a NovaSeq 6000 (Illumina).
  • MAGeCK software version 0.5.8 was used to analyze screen data (Wang et al., Nat. Protoc. 14(3)'.156-780 (2019)).
  • BioID expression vectors were synthesized with codon optimization to alter sgRNA binding sequences (Twist Bioscience).
  • Dependency Map (DepMap) portal data was accessed through depmap.org (Barretina et al., Nature #53:603-7 (2012)), utilizing the CRISPR (Avana) Public 20Q3 through 20Q4 releases.
  • Example 3 Menin inhibition disrupts GIST cell proliferation without apoptosis
  • VTP-50469 To evaluate the cellular phenotypic consequences of VTP-50469 treatment, cell cycle and apoptosis assays were preformed utilizing VTP-50469 and the TKI imatinib as comparator. While imatinib acutely and potently caused G0/G1 cell cycle arrest within 72 hours, eight days of treatment with VTP-50469 lead to a modest increase in the fraction of cells in G0/G1, as illustrated in FIG. 4E; the combination of VTP-50469 with WM-1119 led to more marked disruption of the cell cycle after an 8-day treatment (FIG. 4E).
  • the monotherapy treatment groups showed similar significant reductions in tumor growth compared to vehicle, while the combination groups showed complete cessation of tumor growth.
  • RNA-seq on GIST-T1 xenografts after 5 and 10 days of imatinib and/or VTP-50469 treatment was performed to evaluate for changes in the GIST transcriptional program arising from Menin and/or KIT inhibition in vivo. Although all treatment conditions led to global transcriptional changes compared with vehicle control, greater changes were seen following treatment with VTP-50469 and the combination of imatinib and VTP-50469 at both time points, with the gene expression profile of imatinib treatment more closely correlating with vehicle-treated tumors (FIG. 7E).
  • this disclosure describes treatment of cell line and patient-derived xenografts with TKI, Menin inhibition, or a combination treatment, which demonstrated activity of Menin inhibition as a monotherapy and even greater activity with the combination of TKI and Menin inhibition.
  • tumors in both monotherapy arms regained their growth trajectory, while tumors treated with the Menin inhibition and TKI combination therapy sustained prolonged tumor suppressive effects observed weeks after treatment withdrawal.
  • a PDX model of GIST saw potent anti -tumor activity of Menin inhibition, with histology showing areas of necrosis interspersed with viable tumor.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2022/081587 2021-12-15 2022-12-14 Therapeutic targeting of gastrointestinal stromal tumor (gist) by disrupting the menin-mll epigenetic complex Ceased WO2023114867A2 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU2022410890A AU2022410890A1 (en) 2021-12-15 2022-12-14 Therapeutic targeting of gastrointestinal stromal tumor (gist) by disrupting the menin-mll epigenetic complex
MX2024007201A MX2024007201A (es) 2021-12-15 2022-12-14 Direccionamiento terapeutico del tumor del estroma gastrointestinal (gist) mediante la alteracion del complejo epigenetico de menina-mll.
KR1020247016183A KR20240121720A (ko) 2021-12-15 2022-12-14 메닌-mll 후성유전학적 복합체 파괴에 의한 위장관 기질 종양(gist)의 치료 표적화
US18/717,194 US20250041299A1 (en) 2021-12-15 2022-12-14 Therapeutic targeting of gastrointestinal stromal tumor (gist) by disrupting the menin-mll epigenetic complex
EP22908673.1A EP4447972A4 (en) 2021-12-15 2022-12-14 THERAPEUTIC TARGETING OF A GASTROINTESTINAL STROMAL TUMOR (GIST) BY DISRUPTION OF THE MENINO-MLL EPIGENETIC COMPLEX
IL311862A IL311862A (en) 2021-12-15 2022-12-14 Medical designation of stromal tumor in the gastrointestinal tract through disruption of the menin-mil epigenetic complex
CA3235383A CA3235383A1 (en) 2021-12-15 2022-12-14 Therapeutic targeting of gastrointestinal stromal tumor (gist) by disrupting the menin-mll epigenetic complex
CN202280073517.6A CN118234497A (zh) 2021-12-15 2022-12-14 通过破坏menin-mll表观遗传复合体靶向治疗胃肠道间质瘤(gist)
JP2024533005A JP2025503385A (ja) 2021-12-15 2022-12-14 メニン－ｍｌｌエピジェネティック複合体を破壊することによる消化管間質腫瘍（ｇｉｓｔ）の治療的標的化

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163289943P 2021-12-15 2021-12-15
US63/289,943 2021-12-15

Publications (2)

Publication Number Publication Date
WO2023114867A2 true WO2023114867A2 (en) 2023-06-22
WO2023114867A3 WO2023114867A3 (en) 2023-07-27

Family

ID=86773651

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/081587 Ceased WO2023114867A2 (en) 2021-12-15 2022-12-14 Therapeutic targeting of gastrointestinal stromal tumor (gist) by disrupting the menin-mll epigenetic complex

Country Status (10)

Country Link
US (1) US20250041299A1 (https=)
EP (1) EP4447972A4 (https=)
JP (1) JP2025503385A (https=)
KR (1) KR20240121720A (https=)
CN (1) CN118234497A (https=)
AU (1) AU2022410890A1 (https=)
CA (1) CA3235383A1 (https=)
IL (1) IL311862A (https=)
MX (1) MX2024007201A (https=)
WO (1) WO2023114867A2 (https=)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11976075B2 (en) 2022-03-28 2024-05-07 Isosterix, Inc. Inhibitors of the MYST family of lysine acetyl transferases
WO2025016385A1 (en) * 2023-07-17 2025-01-23 Kura Oncology, Inc. Pharmaceutical compositions comprising a menin inhibitor
WO2025106862A1 (en) * 2023-11-17 2025-05-22 Kura Oncology, Inc. Methods of treating kit positive cancers with a menin inhibitor
US12312359B2 (en) 2016-06-10 2025-05-27 Vitae Pharmaceuticals, Llc Inhibitors of the menin-MLL interaction
WO2025082444A3 (en) * 2023-10-20 2025-06-05 Janssen Pharmaceutica Nv (r) -n-ethyl-5-fluoro-n-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide, formulations and dosage regimens thereof, for use in treating cancer
US12410184B2 (en) 2023-07-17 2025-09-09 Kura Oncology, Inc. Crystalline forms of a menin inhibitor
US12473295B2 (en) 2019-12-19 2025-11-18 Janssen Pharmaceutica Nv Substituted straight chain spiro derivatives
US12564590B2 (en) 2020-04-07 2026-03-03 Syndax Pharmaceuticals, Inc. Combinations of menin inhibitors and CYP3A4 inhibitors and methods of use thereof
US12616682B2 (en) 2025-01-27 2026-05-05 Acerta Pharma B.V. 1-H-pyrrolo[2,3-c]pyridine compounds

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HK1246593A1 (zh) * 2015-06-04 2018-09-14 Kura Oncology, Inc. 用於抑制menin蛋白与mll蛋白的相互作用的方法及组合物
PH12018501955B1 (en) * 2016-03-16 2024-01-24 Kura Oncology Inc Bridged bicyclic inhibitors of menin-mll and methods of use
PL3429591T3 (pl) * 2016-03-16 2023-07-17 Kura Oncology, Inc. Podstawione pochodne tieno[2,3-d]pirymidyny jako inhibitory meniny-mll i metody ich zastosowania
JP2022503792A (ja) * 2018-09-26 2022-01-12 クラ オンコロジー，インク． メニン阻害剤を用いた血液悪性腫瘍の処置

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12312359B2 (en) 2016-06-10 2025-05-27 Vitae Pharmaceuticals, Llc Inhibitors of the menin-MLL interaction
US12473295B2 (en) 2019-12-19 2025-11-18 Janssen Pharmaceutica Nv Substituted straight chain spiro derivatives
US12564590B2 (en) 2020-04-07 2026-03-03 Syndax Pharmaceuticals, Inc. Combinations of menin inhibitors and CYP3A4 inhibitors and methods of use thereof
US11976075B2 (en) 2022-03-28 2024-05-07 Isosterix, Inc. Inhibitors of the MYST family of lysine acetyl transferases
WO2025016385A1 (en) * 2023-07-17 2025-01-23 Kura Oncology, Inc. Pharmaceutical compositions comprising a menin inhibitor
US12410184B2 (en) 2023-07-17 2025-09-09 Kura Oncology, Inc. Crystalline forms of a menin inhibitor
US12521396B2 (en) 2023-07-17 2026-01-13 Kura Oncology, Inc. Pharmaceutical compositions comprising a MENIN inhibitor
WO2025082444A3 (en) * 2023-10-20 2025-06-05 Janssen Pharmaceutica Nv (r) -n-ethyl-5-fluoro-n-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide, formulations and dosage regimens thereof, for use in treating cancer
WO2025106862A1 (en) * 2023-11-17 2025-05-22 Kura Oncology, Inc. Methods of treating kit positive cancers with a menin inhibitor
US12616682B2 (en) 2025-01-27 2026-05-05 Acerta Pharma B.V. 1-H-pyrrolo[2,3-c]pyridine compounds

Also Published As

Publication number Publication date
KR20240121720A (ko) 2024-08-09
IL311862A (en) 2024-06-01
WO2023114867A3 (en) 2023-07-27
EP4447972A4 (en) 2025-12-31
AU2022410890A1 (en) 2024-05-02
JP2025503385A (ja) 2025-02-04
EP4447972A2 (en) 2024-10-23
CN118234497A (zh) 2024-06-21
MX2024007201A (es) 2024-08-06
US20250041299A1 (en) 2025-02-06
CA3235383A1 (en) 2023-06-22

Similar Documents

Publication Publication Date Title
US20250041299A1 (en) Therapeutic targeting of gastrointestinal stromal tumor (gist) by disrupting the menin-mll epigenetic complex
Traweek et al. Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma
Han et al. Phase I/II study of gefitinib (Iressa®) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer
Hemming et al. MOZ and Menin–MLL complexes are complementary regulators of chromatin association and transcriptional output in gastrointestinal stromal tumor
US20240118266A1 (en) Cell death biomarker
WO2018204657A1 (en) Detection of cancer
ES2992827T3 (en) Combination therapies targeting mitochondrial biogenesis for cancer therapy
US20170321281A1 (en) Methods and compositions for treatment of glioblastoma
Marullo et al. XPO1 enables adaptive regulation of mRNA export required for genotoxic stress tolerance in cancer cells
AU2022230312A1 (en) Biomarkers for cancer therapy using mdm2 antagonists
Zhang et al. Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kα inhibitors
Ratz et al. Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer
WO2018167519A1 (en) Biomarker for identifying responders to cancer treatment
TW202202143A (zh) 使用cdk4/6及cdk2抑制劑共同治療以遏止腫瘤對cdk2抑制劑之適應性
US20220288067A1 (en) Treatment of cancer with cdk inhibitors
WO2021176008A1 (en) Agents targeting baf155 or brg1 for use in treatment of advanced prostate cancer
Angel et al. A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers
Lewis et al. RNA Splicing as a Therapeutic Target in Cancer
Li et al. NUP98‐p65 complex regulates DNA repair to maintain glioblastoma stem cells
US20250146080A1 (en) Methods for overcoming tazemetostat-resistance in cancer patients
US20240398814A1 (en) Kras inhibitor and hdac inhibitor combination for the treatment of cancer
Walton et al. PRMT1 is a critical dependency in clear cell renal cell carcinoma through its role in post-transcriptional regulation of DNA damage response genes
Tsai Investigating radiation therapy treatments with cell cycle and DNA repair inhibitors in triple-negative breast cancer
Cullinane et al. Targeting the ribosome to treat multiple myeloma
WO2025090966A1 (en) Mek inhibitors, alone or in combination with cdk4/5 inhibitors, for use in treating cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22908673

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 311862

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 809901

Country of ref document: NZ

Ref document number: AU2022410890

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 3235383

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 202280073517.6

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 2022410890

Country of ref document: AU

Date of ref document: 20221214

Kind code of ref document: A

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22908673

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2024533005

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 18717194

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: MX/A/2024/007201

Country of ref document: MX

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112024011469

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 202491557

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 2022908673

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022908673

Country of ref document: EP

Effective date: 20240715

WWE Wipo information: entry into national phase

Ref document number: 11202403902U

Country of ref document: SG

ENP Entry into the national phase

Ref document number: 112024011469

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20240607