[go: up one dir, main page]

WO2025215527A2 - Combinaisons pharmaceutiques et leurs utilisations - Google Patents

Combinaisons pharmaceutiques et leurs utilisations

Info

Publication number
WO2025215527A2
WO2025215527A2 PCT/IB2025/053691 IB2025053691W WO2025215527A2 WO 2025215527 A2 WO2025215527 A2 WO 2025215527A2 IB 2025053691 W IB2025053691 W IB 2025053691W WO 2025215527 A2 WO2025215527 A2 WO 2025215527A2
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
compound
cancer
wrn
pharmaceutically acceptable
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/IB2025/053691
Other languages
English (en)
Other versions
WO2025215527A3 (fr
Inventor
Marta Cortes-Cros
Stephane FERRETTI
Isabel Cristina JACO
Sandra BLUM-KALLERT
Laurent LABORDE
Katarzyna WNUK-LIPINSKA
Michele MOSCHETTA
Rita ANDRAOS-REY
Ruben De Kanter
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.)
Novartis AG
Original Assignee
Novartis AG
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 Novartis AG filed Critical Novartis AG
Publication of WO2025215527A2 publication Critical patent/WO2025215527A2/fr
Publication of WO2025215527A3 publication Critical patent/WO2025215527A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • 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
    • 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
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical combination comprising a WRN inhibitor in combination with at least one other therapeutic agent.
  • the combination is a WRN inhibitor with an ionising radiation-based therapy, or with carboplatin and paclitaxel.
  • the present invention further relates to methods of treating cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, comprising administering said agents to a subject in need thereof.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • Combinations of drugs can address both these factors by improving overall efficacies and at the same time targeting tumor robustness and complexity to counter resistance (Robert, Karaszewska et al.2015, Turner, Ro et al.2015). It is not yet clear how many drugs are required, and which processes need to be targeted in combination to overcome specific types of cancer. But it is almost certain that different pathways or drivers need to be inhibited, most likely requiring two or more drugs (Bozic, Reiter et al.2013). In spite of numerous treatment options for patients with specific types of cancer, there remains a need for effective and safe combination therapies that can be administered for the treatment of cancer.
  • SUMMARY PAT059671 It is an object of the present invention to provide for a medicament to improve treatment of a cancer, in particular to improve treatment of cancer through inhibition of cell growth (proliferation) and/or induction of apoptosis (cell death). It is another object of the present invention to find novel combination therapies, for example those which selectively synergize the inhibition of proliferation and/or the induction of apoptosis.
  • the present invention provides a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: A.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, or B. carboplatin and paclitaxel.
  • the present invention also provides a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: A. an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, or B. carboplatin and paclitaxel.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • the present invention also provides a pharmaceutical combination comprising a WRN inhibitor and: A. an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, or B. carboplatin and paclitaxel.
  • the present invention provides combination therapies comprising a WRN inhibitor compound of formula (1g), or a pharmaceutically acceptable salt thereof: and wherein R 1 is selected from:
  • a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: .
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: i. carboplatin, and PAT059671 ii. paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: .
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • a method of treating cancer in a subject in need thereof in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof:
  • a method of treating cancer in a subject in need thereof in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: a. carboplatin, and b. paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: .
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • a pharmaceutical combination comprising a.) a WRN inhibitor, and b.) an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: PAT059671 .
  • a pharmaceutical combination comprising a.) a WRN inhibitor, b.) carboplatin and c.) paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: Therefore, according to a seventh aspect of the invention, there is hereby provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of administration of at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA-PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4- quadruplex stabilizer, an ATM inhibitor, a CHK1 or CH
  • a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA-PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4-quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D
  • a pharmaceutical combination comprising a WRN inhibitor and at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA- PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4- quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP/TEAD inhibitor, BCL2 inhibitor, or a BCL2/BCLxl dual inhibitor, a MCL1 inhibitor, a CDK2 inhibitor, CDK4 or dual CDK 4 and 6 inhibitor, a H
  • a WRN inhibitor for use in the treatment of cancer, in particular microsatellite stable (MSS) cancer, wherein the treatment further comprises administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof.
  • Said treatment optionally further comprises administration of irinotecan.
  • a method of treating cancer in a subject in need thereof, in particular microsatellite stable (MSS) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof.
  • Said treatment optionally further comprises administration of irinotecan.
  • a pharmaceutical combination comprising a WRN inhibitor compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and optionally, irinotecan.
  • a WRN inhibitor for example a WRN inhibitor compound of formula (1g) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular microsatellite stable (MSS cancer), wherein the treatment comprises: (a) administration of at least one therapeutically active agent which can create or increase MSI- H status in cancer cells, PAT059671 (b) identification of the presence of microsatellite instability (MSI-H) in a sample from a patient, and (c) administration of a WRN inhibitor, for example a WRN inhibitor compound of formula (1g), or a pharmaceutically acceptable salt thereof.
  • MSS cancer microsatellite stable
  • FIG.1 Efficacy of Compound A in combination with carboplatin and paclitaxel against OVK18 ovarian xenografts in Crl:NU(NCr)-Foxn1 nu mice
  • FIG.2 Tolerability of Compound A in combination with carboplatin and paclitaxel against OVK18 ovarian xenografts in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG.3 Efficacy of Compound A in combination with carboplatin and paclitaxel against JHUEM2 endometrial xenografts in CB17.Cg-PrkcscidLystbg-J/Crl mice.
  • FIG. 4 Tolerability of Compound A in combination with carboplatin and paclitaxel against JHUEM2 endometrial xenografts in CB17.Cg-PrkcscidLystbg-J/Crl mice.
  • FIG.5 Efficacy of Compound A in combination with EBRT against OVK18 ovarian xenografts in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG.6 Tolerability of Compound A in combination with EBRT against OVK18 ovarian xenografts in in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG. 7 Efficacy of Compound A in combination with EBRT against JHUEM2 endometrial xenografts in CB17.Cg-PrkcscidLystbg-J/Crl mice.
  • FIG. 8 Tolerability of Compound A in combination with EBRT against JHUEM2 endometrial xenografts in CB17.Cg-PrkcscidLystbg-J/Crl mice.
  • FIG.9 Efficacy of Compound A in combination with irinotecan against RKO colorectal xenografts in NOD-Rag2 tm1 -IL2rg tm1 /Rj mice.
  • FIG. 10 Tolerability of Compound A in combination with irinotecan against RKO colorectal xenografts in NOD-Rag2 tm1 -IL2rg tm1 /Rj mice
  • FIG 11 Efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel against 4412-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 12 Tolerability of Compound A or Compound C in combination with carboplatin and paclitaxel against 4412-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 13 Efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel against 3200-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 14 Tolerability of Compound A or Compound C in combination with carboplatin and paclitaxel against 3200-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 15 Efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel against 2781-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 16 Tolerability of Compound A or Compound C in combination with carboplatin and paclitaxel against 2781-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 17 Efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel against 20669-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 18 Tolerability of Compound A or Compound C in combination with carboplatin and paclitaxel against 20669-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 19 Efficacy of Compound A or Compound C in combination with EBRT against 4412-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 20 Tolerability of Compound A or Compound C in combination with EBRT against 4412-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 21 Efficacy of Compound A or Compound C in combination with EBRT against 3200-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 22 Tolerability of Compound A or Compound C in combination with EBRT against 3200-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 23 Efficacy of Compound C in combination with EBRT against 2781-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 24 Tolerability of Compound C in combination with EBRT against 2781-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • FIG 25 Efficacy of Compound A or Compound C in combination with EBRT against 20669-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • PAT059671 FIG 26: Tolerability of Compound A or Compound C in combination with EBRT against 20669- HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1 nu mice.
  • an object of the present invention is to find novel combination therapies for the treatment of cancer, in particular cancer characterized as microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR).
  • the combination therapies synergize in inhibiting proliferation and/or in inducing apoptosis.
  • Another object of the invention is to find novel combination therapies for the treatment of cancer, in particular cancer characterized as microsatellite stable (MSS).
  • the combinations of the present invention in particular comprise a WRN inhibitor compound of Formula (1g), or a pharmaceutically acceptable salt thereof: and wherein R 1 is selected from:
  • a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: i. carboplatin, and ii. paclitaxel, and in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: a. carboplatin, and b. paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical combination comprising a.) a WRN inhibitor, and b.) an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, PAT059671 in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical combination comprising a.) a WRN inhibitor, b.) carboplatin and c.) paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof.
  • a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer
  • the treatment further comprises administration of administration of at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA-PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4-quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP/TEAD inhibitor, BCL2 inhibitor, or a BCL2/
  • a therapeutically active agent selected from the group consisting of
  • a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent selected from the group consisting PAT059671 of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA-PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4-quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS
  • a pharmaceutical combination comprising a WRN inhibitor and at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA- PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4- quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP/TEAD inhibitor, BCL2 inhibitor, or a BCL2/BCLxl dual inhibitor, a MCL1 inhibitor, a CDK2 inhibitor, CDK4 or dual CDK 4 and 6 inhibitor, a HIF2
  • a WRN inhibitor for use in the treatment of cancer, in particular microsatellite stable (MSS) cancer, wherein the treatment further comprises administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof.
  • Said treatment optionally further comprises administration of irinotecan.
  • a method of treating cancer in a subject in need thereof, in particular microsatellite stable (MSS) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof.
  • Said treatment optionally further comprises administration of irinotecan.
  • a pharmaceutical combination comprising a WRN inhibitor compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and optionally, irinotecan.
  • a WRN inhibitor for example a WRN inhibitor compound of formula (1g) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular microsatellite stable (MSS cancer), wherein the treatment comprises: (a) administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, (b) identification of the presence of microsatellite instability (MSI-H) in a sample from a patient, and (c) administration of a WRN inhibitor, for example a WRN inhibitor compound of formula (1g), or a pharmaceutically acceptable salt thereof.
  • MSS cancer microsatellite stable
  • the cancer is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), in particular microsatellite instability- high (MSI-H).
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • PAT059671 In an embodiment of any of the first, third or fifth aspects of the invention, the ionising radiation is external beam radiation.
  • the cancer is selected from: ⁇ colorectal cancer (CRC), such as colon adenocarcinoma or rectal adenocarcinoma, ⁇ gastric cancer, such as stomach adenocarcinoma, ⁇ prostate cancer, ⁇ endometrial cancer, ⁇ adrenocortical cancer, such as adrenocortical carcinoma, ⁇ cervical cancer, such as cervical squamous cell carcinoma or endocervical adenocarcinoma, ⁇ uterine cancer, such as uterine corpus endometrial carcinoma and uterine carcinosarcoma, ⁇ esophageal ccancer, such as esophageal carcinoma, ⁇ breast cancer, such as breast carcinoma or triple negative breast cancer, ⁇ kidney cancer, such as kidney renal clear cell carcinoma, ⁇ ovarian cancer, such as ovarian serous cystadenocarcinoma, ⁇ glioma, ⁇ glioblastoma, ⁇
  • CRC color
  • the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof: PAT059671 .
  • the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6- ((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7- methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof: .
  • the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof:
  • the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4- (5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in non-zwitterionic form: or zwitterionic form: PAT059671 or a mixture of any two or three of said forms.
  • the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6- ((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7- methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in non-zwitterionic form or in zwitterionic form: PAT059671 or a mixture of any two or three of said forms.
  • the WRN inhibitor is compound C, in non-zwitterionic form: PAT059671 or zwitterionic form: or a mixture of any two or three of said forms.
  • a WRN inhibitor for use in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular ovarian or endometrial cancer wherein the treatment further comprises administration of an external beam radiation, and wherein the WRN inhibitor is compound A PAT059671 pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: .
  • a WRN inhibitor for use in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular ovarian or endometrial cancer, wherein the treatment further comprises administration of: i. carboplatin, and ii. paclitaxel, and the WRN inhibitor is:
  • WRN inhibitor for use in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular colorectal cancer, wherein the treatment further comprises administration of irinotecan, and the WRN inhibitor is: pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: .
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • a WRN inhibitor for use in the treatment of microsatellite stable (MSS) cancer, wherein the treatment further comprises PAT059671 administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein: i. the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and ii.
  • the agent which can create or increase MSI-H status in cancer cells is temozolomide, cisplatin or 6-thioguanine, or is an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical, and optionally, iii. said treatment further comprises administration of irinotecan.
  • a method of treating microsatellite stable (MSS) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein: i.
  • the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and ii.
  • the agent which can create or increase MSI-H status in cancer cells is temozolomide, cisplatin or 6-thioguanine, or is an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical, and optionally, iii. said treatment further comprises administration of irinotecan.
  • Embodiment 1 Embodiment 1.
  • a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer wherein the treatment further comprises administration of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, PAT059671 and wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof: and wherein R 1 is selected from: R 16 is R 25 (R 24 )N-; R 17 is F; R 18 is F; R 19 is F; R 20 is F; R 21 is CH 3 ; PAT059671 R 22 is CF 3 , CHF 2 CH 2 , HOC(O)-CH 2 -, H 3 C-C(O)-, (H 3 C) 3 C-O-C(O)-; R 23 is CF 3 , CHF 2 CH 2 -, (H 3 C) 3 C-O-C(O
  • Embodiment 2 A WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: i. carboplatin, and PAT059671 ii. paclitaxel, and wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof Embodiment 4.
  • a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: a. carboplatin, and b. paclitaxel wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, PAT059671 or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • a combination comprising a.) a WRN inhibitor, and b.) an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof.
  • the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof.
  • a combination comprising a.) a WRN inhibitor, b.) carboplatin and c.) paclitaxel, wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 7 The WRN inhibitor for use according to embodiment 1 or embodiment 2, or the method according to embodiment 3 or embodiment 4, or the combination according to embodiment 5 or embodiment 6, wherein the cancer is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • PAT059671 Embodiment 9 The WRN inhibitor for use according to any of embodiments 1, 2, 7 or 8, or the method according to any of embodiments 3, 4, 7 or 8, or the combination according to any of embodiments 5, 6, 7 or 8, wherein the cancer is selected from: ⁇ colorectal cancer (CRC), such as colon adenocarcinoma or rectal adenocarcinoma, ⁇ gastric cancer, such as stomach adenocarcinoma, ⁇ prostate cancer, ⁇ endometrial cancer, ⁇ adrenocortical cancer, such as adrenocortical carcinoma, ⁇ cervical cancer, such as cervical squamous cell carcinoma or endocervical adenocarcinoma, ⁇ uterine cancer, such as uterine corpus endometrial carcinoma and
  • Embodiment 10 The WRN inhibitor for use according to embodiment 9, or the method according to embodiment 9, or the combination according to embodiment 9, wherein the cancer is colorectal cancer (CRC), ovarian cancer or endometrial cancer.
  • Embodiment 11 The WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 10, or the method according to any of embodiments 3, 4 or 7 to 10 , or the combination according to any of embodiments 5, 6 or 7 to 10, wherein the WRN inhibitor is (7R,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4- PAT059671 carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2- c][1,2,4]triazolo[1,5-a]pyrimidine-9-
  • Embodiment 12 The WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 10, or the method according to any of embodiments 3, 4 or 7 to 10, or the combination according to any of embodiments 5, 6 or 7 to 10, wherein the compound is (7R,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof: .
  • Embodiment 13 The WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 10, or the method according to any of embodiments 3, 4 or 7 to 10, or the combination according to any of embodiments 5, 6 or 7 to 10, wherein the compound is (7R,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4- PAT059671 carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2- c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in non-zwitterionic form: or zwitterionic form:
  • the WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 10, or the method according to any of embodiments 3, 4 or 7 to 10, or the combination according to any of embodiments 5, 6 or 7 to 10, wherein the compound is (7R,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in non-zwitterionic form
  • Embodiment 16 A WRN inhibitor for use in the treatment of microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR) cancer, in particular colorectal, ovarian or endometrial cancer, wherein the treatment further comprises administration of an external beam radiation, and wherein the WRN inhibitor is compound A PAT059671 pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: .
  • MSI- H microsatellite instability-high
  • dMMR mismatch repair deficient
  • PAT059671 wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: Embodiment 18.
  • PAT059671 Embodiment 19 Embodiment 19.
  • MSS microsatellite stable
  • a method of treating cancer in a subject in need thereof, in particular microsatellite stable (MSS) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and said treatment optionally further comprises administration of irinotecan.
  • MSS microsatellite stable
  • a pharmaceutical combination comprising a WRN inhibitor compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and optionally, irinotecan.
  • a WRN inhibitor compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof and at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and optionally, irinotecan.
  • a WRN inhibitor for example a WRN inhibitor compound of formula (1g) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular microsatellite stable (MSS cancer), wherein the treatment comprises: (a) administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, (b) identifying the presence of microsatellite instability (MSI-H) in a sample from a patient, and (c) administration of a WRN inhibitor, for example a WRN inhibitor compound of formula (1g), or a pharmaceutically acceptable salt thereof.
  • MSS cancer microsatellite stable
  • the WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 17, or the method according to any of embodiments 3, 4 or 7 to 17, or the combination according to any of embodiments 5, 6 or 7 to 17, wherein the combination partners the WRN inhibitor, carboplatin and paclitaxel, or the combination partners the WRN inhibitor and ionising radiation-based therapy, are provided in synergistically effective amounts for the treatment of MSI-H cancer, in particular for the treatment of endometrial or ovarian cancer.
  • the WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 17, or the method according to any of embodiments 3, 4 or 7 to 17, or PAT059671 the combination according to any of embodiments 5, 6 or 7 to 17, wherein the combination partners the WRN inhibitor, carboplatin and paclitaxel, or the combination partners the WRN inhibitor and ionising radiation-based therapy, are jointly therapeutically effective for the treatment of MSI-H cancer, in particular endometrial or ovarian cancer.
  • a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one PD-1 inhibitor.
  • a pharmaceutical combination comprising a.) a WRN inhibitor, and b.) at least one PD-1 inhibitor.
  • the PD-1 inhibitor is an anti-PD-1 antibody.
  • the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), Cemiplimab (REGN2810, Regeneron), Dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), Balstilimab (AGEN2035, Agenus), Sintilimab (InnoVent), Toripalimab (Shanghai Junshi Bio
  • the PD-1 inhibitor is tislelizumab or pembrolizumab, in particular pembrolizumab.
  • Compound A refers to the compound of Example 21A of PCT/IB2023/060166 (WO2024/079623) and US18/483651 (US2024-0245694): Compound A (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo- 5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide.
  • Compound A is a preferred compound of formula (1g).
  • the term “Compound B” refers to the compound of Example 18A of PCT/IB2023/060166 (WO 2024/079623).
  • PAT059671 Compound B (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide.
  • Compound C refers to the compound of Ex 42 / Ex123 as described in PCT/IB2022/054850 (WO 2022/249060), or US 2023-0046859, which are hereby incorporated by reference in their entirety N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)- yl)acetamide.
  • “Combination” or “pharmaceutical combination” refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration, or a combined administration, for example where a WRN inhibitor, such as a compound of formula (1g), or Compound C, or a pharmaceutically acceptable salt thereof, and a combination partner (e.g. another drug as explained herein, also referred to as “therapeutic agent” or “co-agent”) may be administered PAT059671 independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a WRN inhibitor such as a compound of formula (1g), or Compound C, or a pharmaceutically acceptable salt thereof
  • a combination partner e.g. another drug as explained herein, also referred to as “therapeutic agent” or “co-agent”
  • a combination partner e.g. another drug as explained herein, also referred to as “therapeutic agent” or “co
  • the combination partner for the WRN inhibitor such as the compound of formula (1g), or Compound C, may also for example be an agent that is capable of sensitising or priming the cancer cells to treatment, for example for an improved response to treatment with a WRN inhibitor.
  • the single components may be packaged in a kit or separately.
  • One or both of the components e.g., powders or liquids
  • co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents.
  • fixed combination means that the therapeutic agents, e.g. combination partners of the present invention, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the therapeutic agents, e.g. combination partners of the present invention, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient, or one agent provides a sensitizing or priming effect before or during treatment with a combination partner.
  • cocktail therapy e.g. the administration of three or more therapeutic agents.
  • the therapeutic agents may be manufactured and/or formulated by the same or different manufacturers.
  • the therapeutic agents may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the therapeutic agents); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the therapeutic agents.
  • Pre-treatment means administration separately and prior to administration of certain other active compounds, in particular the WRN inhibitor.
  • pre-treatment may sensitise or prime the cancer cells to be more responsive or sensitive to the active compound(s) subsequently administered.
  • Pre-treatment may be used for example to increase MMR deficiency, or may be used to increase resistance of cancer cells to the the pre-treatment agent.
  • Pre-treatment may be PAT059671 used to create or increase MSI-H status in cancer cells, create or increase MMR deficiency in cancer cells, or increase MMR heterogeneity of cancer cells.
  • Temozolomide can be used herein as a pre-treatment agent to sensitise or prime the cancer cells to subsequent treatment, in particular to subsequent treatment with a WRN inhibitor.
  • Such effects may also occur when the agent such as temozolomide is used directly in combination with a WRN inhibitor, without pre-treatment administration in advance.
  • the effects of such-pre-treatment may be determined according to tests taught in the art, or tests commercially available, or an FDA- approved test.
  • the pre-treatment may be for example using an agent selected from temozolomide, cisplatin and 6-thioguanine, or the agent may be an ionising radiation based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical).
  • synergistic effect refers to action of two or three therapeutic agents producing an effect, for example, slowing the progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet.6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol.114: 313-326 (1926)) and the median effect equation (Chou, T. C.
  • Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of a drug combination.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable.
  • the compound may be capable of forming acid addition salts by virtue of the presence of an amino group.
  • reference to therapeutic agents useful in the pharmaceutical combination of the present invention includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds.
  • the term “combination” or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the therapeutic agents may be administered together, independently at the same time or separately within time intervals, which preferably allows that the combination PAT059671 partners show a cooperative, e.g. synergistic effect.
  • the single compounds of the pharmaceutical combination of the present invention could be administered simultaneously or sequentially.
  • the pharmaceutical combination of the present invention may be in the form of a fixed combination or in the form of a non-fixed combination.
  • the term “fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are in the form of a single entity or dosage form.
  • the term “non-fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time limits, wherein preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the subject, e.g., a mammal or human in need thereof.
  • the pharmaceutical combinations can further comprise at least one pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the pharmaceutical combination of the present invention and at least one pharmaceutically acceptable carrier.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
  • compositions are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutical composition is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human.
  • the present pharmaceutical combinations can be formulated in a suitable pharmaceutical PAT059671 composition for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units.
  • the pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).
  • One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden.
  • the amount of each carriers used may vary within ranges conventional in the art.
  • the following references disclose techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003).
  • These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form.
  • the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet.
  • the pharmaceutical combinations of the present invention can be used to manufacture a medicine.
  • the present invention relates to such pharmaceutical combinations or pharmaceutical compositions that are particularly useful as a medicine.
  • the combinations or compositions of the present invention can be applied in the treatment of cancer.
  • the present invention also relates to use of pharmaceutical combinations or pharmaceutical compositions of the present invention for the preparation of a medicament for the treatment of a cancer, and to a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to the present invention, or the pharmaceutical composition according to the present invention.
  • treatment comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • treatment also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease in a patient, e.g., a mammal, particularly the patient is a human.
  • treatment as used herein comprises an inhibition of the growth of a tumor incorporating a direct inhibition of a primary tumor growth and / or the systemic inhibition of metastatic cancer cells.
  • a “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, simians, humans, farm animals, sport animals, and pets.
  • the term "a therapeutically effective amount" of a compound (e.g. chemical entity or biologic agent) of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “therapeutically effective agent” or “therapeutic agent” as used herein is intended to be construed broadly and includes both drug molecules and ionising radiation based therapies.
  • the ionizing radation based therapy may be provided in any suitable form known in the art, for example in the form of an external beam radiation therapy, brachytherapy or via a radiopharmaceutical (such as a radioligand agent).
  • External beam radation therapy refers to wherein radiation is directed at the tumor from a source outside of the body.
  • brachytherapy refers to a form of radiation therapy whereby a radiation source is positioned at the tumor site, enabling a high dose of localized radiation to be administration to that tumor site. Radiopharmaceuticals are discussed in more detail below.
  • each combination partner for treatment of a cancer can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art.
  • the amount of each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration.
  • the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone.
  • Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
  • the combination of the present invention may, for example, be in unit dosage of about 1-1000 mg of each active ingredient for a subject of about 50-70 kg.
  • ‘Zwitterion’ or ‘zwitterionic form’ means a compound containing both positive and negatively charged functional groups.
  • the compound of formula (1g) described herein can include the following forms, wherein R 4 is the zwitterionic form (c) or non-zwitterionic form (d), mixture thereof.
  • the compound of formula (1g) or Compound C, described herein can also include the following forms, wherein R 4 is the zwitterionic form (a) or (b) or the non-zwitterionic form (e), PAT059671 or a mixture of two thereof, or a mixture of all three thereof.
  • a ‘compound of formula (1g)’, or ‘Compound C’ includes zwitterionic and non-zwitterionic forms, and mixtures thereof.
  • halo means fluoro, chloro or bromo, particularly fluoro or chloro.
  • Alkyl, and alkoxy groups, containing the requisite number of carbon atoms, can be unbranched or branched.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, sec-butyl and t-butyl.
  • cancer refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body.
  • cancers examples include but are not limited to colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian cancer and the like.
  • tumor and cancer are used interchangeably, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors.
  • cancer or “tumor” includes premalignant, as well as malignant cancers and tumors.
  • WRN inhibitor’ or ‘WRN helicase inhibitor’ as used herein means a compound or therapeutic agent that inhibits Werner Syndrome RecQ DNA helicase (WRN).
  • WRN refers to the protein of Werner Syndrome RecQ DNA helicase.
  • WRN includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN.
  • the protein is encoded by the WRN gene (Entrez gene ID 7486; Ensembl ID ENSG00000165392).
  • Exemplary WRN sequences are available at the Uniprot database under accession number Q14191.
  • PAT059671 WRN inhibitors are known in the art.
  • the WRN inhibitor may be a compound of formula (I), (1a) or (1g) as described in WO2022/249060, for example as described in embodiment 1 or claim 1.
  • the WRN inhibitor may alternatively be a compound of formula (I) or (1g) as described in WO2024/079623, for example as described in embodiment 1 or claim 1.
  • Disease or condition mediated by WRN includes a disease or condition, such as cancer, which is treated by WRN inhibition.
  • this can include cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • MSI-H ‘Microsatellite unstable cancer’, microsatellite instability-high cancer’, ‘microsatellite high cancer’ and ‘MSI-high cancer’ ‘MSI hi ’ and ‘MSI-H’ when used herein, are used interchangeably, and describe cancers that have a high number of alterations in the length of simple repetitive genomic sequences within microsatellites.
  • the determination of MSI-H or dMMR tumor status for patients can be performed using, e.g., polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Methods for identification of MSI-H or dMMR tumor status are described, e.g., in Ryan et PAT059671 al.
  • pMMR means proficient mismatch repair.
  • pMMR/MSS means “MSS cancer” or “pMMR cancer”. MSS cancer cells are proficient for MMR (pMMR), thus the terms “MSS cancer” or “pMMR cancer” can be used separately and interchangeably.
  • Microsatellite instability is present in various cancers, including but not limited to colorectal cancer, gastric cancer and endometrial cancer in particular, but also in adrenocortical, uterine, cervical, esophageal, breast, kidney, prostate and ovarian cancers.
  • microsatellite high cancers include uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma.
  • a cancer that has “defective mismatch repair” (dMMR) or “dMMR character” includes cancer types associated with documented MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1 mutations or epigenetic silencing, microsatellite fragile sites, or other gene inactivation mechanisms, including but not limited to cancers of the lung, breast, kidney, large intestine, ovary, prostate, upper aerodigestive tract, stomach, endometrium, liver, pancreas, haematopoietic and lymphoid tissue, skin, thyroid, pleura, autonomic ganglia, central nervous system, soft tissue, pediatric rhabdoid sarcomas, melanomas and other cancers.
  • dMMR defective mismatch repair
  • a cell or cancer with “defective” mismatch repair has a significantly reduced (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90% decrease) amount of mismatch repair.
  • a cell or cancer which is defective in mismatch repair will perform no mismatch repair.
  • the invention herein provides combinations comprising a WRN inhibitor compound of Formula (1g) or Compound C, in particular Compound A or Compound C, or a pharmaceutically acceptable salt thereof, or Compound B or a pharmaceutically acceptable salt thereof, with another therapeutically active agent. Examples of therapeutically active agents as combinations partners for the WRN inhibitor compound of Formula (1g) or Compound C are provided below.
  • the therapeutically active agent is a chemotherapy agent.
  • the chemotherapy agent is selected from anastrozole (Arimidex®), vinblastine, vindesine, vinorelbine, vincristine, bicalutamide (Casodex®), bleomycin (e.g.
  • bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), calactin, capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), lomustine (CCNU®), chlorambucil (Leukeran®), bendamustine (Treanda®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunor
  • doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), a mitomycin (e.g.
  • the chemotherapy agent is selected from gemcitabine, camptothecin, irinotecan (Camptosar®), docetaxel (Taxotere®), doxorubicin (e.g. doxorubicin hydrochloride) (Adriamycin®, Rubex®), 5-fluorouracil (Adrucil®, Efudex®), capecitabine (Xeloda®), etoposide (Vepesid®), epirubicin (Ellence®, Pharmorubicin®), oxaliplatin (Eloxatin®), mitomycin (e.g.
  • the chemotherapy agent is selected from 5-fluorouracil, cisplatin, bleomycin, docetaxel, epirubicin, etoposide, camptothecin, mitomycin, oxaliplatin, mitomycin (e.g. mitomycin C) and gemcitabine.
  • the therapeutically active agent is a WEE1 inhibitor.
  • the WEE1 inhibitor is selected from Adavosertib (also known as AZD1775 and MK- 1775) and PDO166285. In an embodiment, the WEE1 inhibitor is Adavosertib (also known as AZD1775 and MK-1775).
  • the therapeutically active agent is an ATR inhibitor. In an embodiment, the ATR inhibitor is selected from RP-3500, ceralasertib (also known as AZD6738), berzosertib, ART-0380, gartisertib (also known as M4344), and elimusertib (also known as BAY- 1895344).
  • the ATR inhibitor is elimusertib (BAY-1895344).
  • the therapeutically active agent is a DNA-PK inhibitor.
  • the DNA-PK inhibitor is selected from AZD-7648, NU7441 (also known as KU- 57788), Omipalisib, BAY8400 and M3814.
  • the DNA-PK inhibitor is AZD-7648 or NU7441 (KU-57788), particularly AZD-7648.
  • the therapeutically active agent is a ionising radiation based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical.
  • the ionising radiation is external beam radiation.
  • the ionising radiation is a radiopharmaceutical.
  • the radiopharmaceutical is a radioligand agent.
  • the radioligand agent is selected from 177 Lu-PSMA-617, 177 Lu-PSMA-R2, 177 Lu-NeoB, and 177 Lu-FAP-2286.
  • the therapeutically active agent is a MEK inhibitor.
  • the MEK inhibitor is selected from the group consisting of refametinib, pimasertib, selumetinib, trametinib, binimetinib and cobimetinib, or a pharmaceutically acceptable salt thereof.
  • the MEK inhibitor is trametinib.
  • the therapeutically active agent is an MDM2 inhibitor.
  • the MDM2 inhibitor is selected from the group consisting of nutlin-3a, idasanutlin (also known as RG7388), RG7112, KRT-232 (also known as AMG-232), APG-115, RAIN-32 (also known as DS-3032 and milademetan), BI-907828 and HDM201 (also known as siremadlin), or a pharmaceutically acceptable salt thereof.
  • the MDM2 inhibitor is HDM201.
  • the therapeutically active agent is a G4-quadruplex stabilizer.
  • the G4-quadruplex stabilizer is pyridostatin. PAT059671
  • the therapeutically active agent is an ATM inhibitor.
  • the ATM inhibitor is selected from KU-55933, KU-60019, KU-59403, M3541, CP- 466722, AZ31, AZ32, AZD0156 and AZD1390.
  • the ATM inhibitor is KU-60019.
  • the therapeutically active agent is a PARP inhibitor.
  • the PARP inhibitor is selected from olaparib, NMS293, niraparib, prexasertib, veliparib, rucaparib, talazoparib, AZD-5305 and KU0058948.
  • the PARP inhibitor is olaparib.
  • the therapeutically active agent is a chemotherapy agent, and the chemotherapy agent is a topoisomerase inhibitor.
  • the topoisomerase inhibitor is selected from QAP1, irinotecan, topotecan, camptothecin and etoposide.
  • the topoisomerase inhibitor is selected from QAP1, etoposide and irinotecan.
  • the therapeutically active agent is a CHK1 or CHK2 inhibitor.
  • the CHK1 or CHK2 inhibitor is selected from GDC-0575, Prexasertib (also known as LY2606368), SCH900776 (also known as MK-8776), SRA737, PF477736, LY2606368 and AZD7762.
  • the therapeutically active agent is a DNA polymerase alpha inhibitor, for example aphidicolin.
  • the therapeutically active agent is a PI3K inhibitor, e.g. a PI3K- alpha inhibitor.
  • the PI3K inhibitor is selected from AMG511, buparlisib, Idelalisib, Copanlisib, Duvelisib, Alpelisib, and Umbralisib.
  • the PI3K inhibitor is Alpelisib.
  • the PI3K inhibitor is a PI3K-alpha inhibitor selected from RLY- 2608, BPI-21668, PF-06843195, LX-086, HS-10352, HH-CYH33, JS-105, MEN-1611, LOX- 22783, TOS-358, STX-478, Alpelisib, Serabelisib and Inavolisib.
  • the PI3K- alpha inhibitor is selected from Alpelisib, Serabelisib and Inavolisib.
  • the therapeutically active agent is a polymerase theta inhibitor, for example RP-2119 or Pol Theta Helicase Inhibitor (Ideaya / GSK).
  • the therapeutically active agent is an IAP inhibitor or an SMAC mimetic.
  • the IAP inhibitor is selected from LCL161, Bininapant and Xevinapant.
  • the therapeutically active agent is a CTLA-4 inhibitor, for example ipilimumab.
  • the therapeutically active agent is a KRAS G12C inhibitor, for example a compound selected from sotorasib, adagrasib, GDC6036, D-1553, and in particular, JDQ443. JDQ443 is described in Example 1 of PCT application WO2021/124222, published 24 June 2021. WO2021/124222 is hereby incorporated by reference in its entirety.
  • the therapeutically active agent is a KRAS G12D inhibitor, for example siG12D LODER, HRS-4642 and ASP-3082.
  • the therapeutically active agent is a YAP/TEAD inhibitor.
  • YAP/TEAD inhibitors examples include IAG933 (Novartis), NSC-682769 (University of California), MSC-4106 (Merck), GNE-7883 (Genentech), TED-347 (Indiana University), K-975 (Kyowa Kirin) and the compounds in WO 2021/186324, WO2022/087008; WO2021/102204; WO2020/214734; WO2020/097389; WO2019/222431; WO2019/113236; WO2019/040380; WO2018/204532; WO2017/058716; WO2022/159986; WO2022/120354; WO2022/120355; WO2022/120353; WO2020/243423 or WO2020/243415.
  • the therapeutically active agent is a BCL2 inhibitor, or a BCL2/BCLxl dual inhibitor.
  • BCL2 inhibitor or a BCL2/BCLxl dual inhibitor.
  • examples include venetoclax, APG-2575 (lisaftoclax), obatoclax meylate, BGB-11417 (Beigene), pelcitoclax, Zn-d5 (Zentalis), AZD-0466 (Astra Zeneca), ABBV- 453, ABBV-167 (AbbVie), LP-118, LP-108, (Guangzhou Lupeng), FCN-338 (Fochon Pharmaceuticals) and navitoclax.
  • the therapeutically active agent is a MCL1 inhibitor.
  • the therapeutically active agent is a CDK2 inhibitor, for example BLU222 (Blueprint Medicines), PF-07104091 (Pfizer) and INCB-0123667 (Incyte).
  • the therapeutically active agent is a CDK2/CDK9 or CDK2/CDK9/CDK7 inhibitor, for example fadraciclib and seliciclib.
  • the therapeutically active agent is a CDK4 or CDK4/6 inhibitor. Examples include ribociclib, palbociclib, trilaciclib, birociclib and lerociclib.
  • the therapeutically active agent is a HIF2 alpha inhibitor. Examples include belzutifan, MK-6482, PT2385 and DFF332. PAT059671
  • the therapeutically active agent is a PLK1 inhibitor, such as volasertib.
  • the therapeutically active agent is a SHP2 inhibitor, for TNO155, JAB3312 or JAB-3068 (Jacobio), RLY1971 (Roche), SAR442720/RMC-4630 (Sanofi/Revolution Medicines), RMC4450 (Revolution Medicines), BBP398 (Navire), BR790 (Shanghai Blueray), SH3809 (Nanjing Sanhome), PF0724982 (Pfizer), ERAS601 (Erasca), RX- SHP2 (Redx Pharma), ICP189 (InnoCare), HBI2376 (HUYA Bioscience), ETS001 (Shanghai ETERN Biopharma), HS-10381 (Hansoh Pharma / Jiangsu Hansoh), BPI-442096 (Betta Pharmaceuticals), I-0436650 (IRBM), PCC-0208023 (Binzhou Medical University), IACS-15414 (Navire) and X-37-SHP2 (X-37).
  • SHP2 inhibitor for TNO
  • a particularly preferred SHP2 inhibitor for use according to the invention is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-amine (TNO155), or a pharmaceutically acceptable salt thereof.
  • TNO155 is synthesized according to example 69 of WO2015/107495, which is hereby incorporated by reference in its entirety.
  • a preferred salt of TNO155 is the succinate salt.
  • the therapeutically active agent is a PRMT5 inhibitor, such as SCR-6277, AMG-193, SKL-27969, MRTX-1719, onametostat/JNJ-64619178, TNG-90 and PF- 0693999.
  • the therapeutically active agent is a STING agonist, such as CDK-002, TAK-500, ONO-7914, VB-85247, KL-340399, TAK-676, SNX-281, SB-11285 and IMSA-101.
  • the therapeutically active agent is a TRAIL receptor agonist, such as drozitumab, PRO-95780, CS-1008, IGM-8444, and lexatumumab.
  • the therapeutically active agent is a TAK1 inhibitor, such as takinib.
  • the therapeutically active agent is a MK2 inhibitor, such as CC-99677.
  • the therapeutically active agent is a HDAC inhibitor such as panobinostat, vorinostat, romidepsin, or belinostat.
  • the therapeutically active agent is an androgen biosynthesis inhibitor, such as abiraterone, or an androgen receptor modulator, such as enzalutamide.
  • an androgen biosynthesis inhibitor such as abiraterone
  • an androgen receptor modulator such as enzalutamide.
  • Therapeutically active agents which can create or increase MSI-H status in cancer cells, are known in the art.
  • the agent can for example be an agent such as temozolomide, cisplatin, 6- thioguanine, or an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical.
  • Said agent may be adminsistered at the same time as the WRN inhibitor, or before the WRN inhibitor administration, as a pre-treatment.
  • a therapeutically active agent which can create or increase MSI-H status in cancer cells includes an agent that is shown to create or increase MSI-H status in cells, using a test known in the art.
  • the combination partner for the WRN inhibitor compound of formula (1g), or Compound C may include, for example, an agent that is capable of sensitising or priming the cancer cells to treatment.
  • the combination partner may therefore be used, for example, to: ⁇ sensitise the cancer cells, for example for an improved response to treatment with a WRN inhibitor, ⁇ prime the cancer cells, for example, such priming may include triggering hypermutation status in cancer cells, ⁇ create or increase MMR deficiency in cancer cells, ⁇ create or increase MSI-H status in cancer cells, ⁇ increase MMR heterogeneity of cancer cells, and/or ⁇ create or increase resistance in cancer cells to temolozolomide.
  • These effects may be determined according to tests taught in the art, or tests commercially available, or tests approved by the FDA.
  • Such therapeutic agents are known in the art.
  • Said therapeutic agent may be an alkylating agent, for example temozolomide.
  • Said therapeutic agent may also be cisplatin or 6-thioguanine.
  • Said therapeutic agent may also be an ionising radiation based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical, for example as described herein.
  • PAT059671 Priming, or pre-treatment, with temozolomide may be performed in patients with MSS cancer, or in patients with MGMT-defective, or MGMT-deficient, or MGMT-silenced tumors.
  • Such priming may take place in patients with pMMR/MSS MGMT-defective, or pMMR/MSS MGMT-deficient, or pMMR/MSS MGMT-silenced.tumors.
  • the tumor is MGMT-defective, or MGMT- deficient, or MGMT-silenced CRC.
  • the tumor is pMMR/MSS and MGMT-silenced mCRC.
  • the tumor is MGMT-methylated glioblastoma.
  • MGMT means O 6 -methylguanine DNA methyltransferase.
  • MGMT refers to the gene encoding MGMT.
  • the MGMT gene encodes a repair protein (MGMT; formerly also termed alkyl guanine alkyltransferase) that removes DNA alkylation modifications from DNA.
  • MGMT formerly also termed alkyl guanine alkyltransferase
  • Alkylating chemotherapeutic agents such as TMZ (temozolomide) induce cytotoxic cell death in tumor cells by alkylating DNA at multiple sites. Repair of the most toxic event, alkylation of the O 6 group of guanine, is dependent on MGMT.
  • Assessment of MGMT tumor status can be for example by protein expression promoter methylation, as described in the references below which are hereby incorporated by reference in their entirety, or also by MGMT gene mutations.
  • Radiopharmaceutical refers to a pharmaceutical drug comprising one or more radioactive isotopes configured such that the radioactive isotopes are preferentially delivered to the tumor site.
  • the radiopharmaceutical can simply be a radioactive isotope or a pharmaceutically acceptable salt thereof.
  • 223 Ra-Radium Dichloride BAY88-8223, Xofigo® previously known as 223 Ra-Alpharadin
  • Bayer Pharma is an approved medication for the treatment of cancer types that commonly metastasize to the bone.
  • the radium is preferentially delivered to the bone as a result of its chemical similarity to calcium.
  • iodine salts based on 131 I usually in the form of Sodium Iodide
  • 32 P- Sodium Phosphate used in the palliation of bone pain
  • 153 Sm-Lexidronam pentasodium 153 Sm- Samarium Ethylene Diamine Tetramethylene Phosphoric Acid
  • 153 Sm-Samarium EDTMP Quadramet®
  • 153 Sm-DOTMP CycloSAMTM
  • 153 Sm-Oxabiphor 153 Sm-Samarium oxa- bis(ethylenedithio) tetramethylphosphonium acid
  • 153 Sm-OXB 153 Sm-Oxabifor
  • 153 Sm-ETMP used for the relief of bone pain in patients with multiple osteoblastic skeletal metastases
  • 166 Ho- Phytate used for the potential treatment of chronic synovitis
  • the radioactive isotope is combined with a targeting vector intended to drive the radionuclide to the target.
  • a targeting vector intended to drive the radionuclide to the target.
  • the combination of such a radioactive isotope and a targeting vector is referred to herein as a "radioligand agent”.
  • the radionuclide is selected on the basis of the application of the drug (diagnostic or therapeutic agent), of the type of radiation and of its energy.
  • the targeting vector is intended to drive the radionuclide preferentially to the target tissue, target organ or target cell and can be chemical molecules, peptides, polypeptide, proteins (such as antibodies, antigen binding fragments, Bispecific Antibodies, affibodies, or Fibronectin type III PAT059671 domains), peptidomimetics, fusion proteins/polypeptides, Aptamers, Antisense oligonucleotides, siRNA, microparticles or nanoparticles.
  • chemists may have to develop special chemical structures called linkers.
  • the linkers may be inert moieties used to increase the distance of binding moieties from chelators in order to prevent steric influence and loss of activity on the cell receptors upon functionalization.
  • the length and composition of the linker may influence the binding affinity of the radiopharmaceutical to the receptor, the accumulation of radionuclides in tumor cells and the pharmacokinetic. Direct binding through so-called ‘covalent’ bonds is possible, e.g. with radionuclides such as the radiohalogens 131 I or 211 At.
  • Radiometals may need a so-called ‘chelator’, or “chelating agent”, a molecule moiety in form of a cage that can trap the radiometal.
  • chelating agents include but not limited to DOTA, DTPA, AAZTA, TCMC, DAT, DFO, DOTAGA, DOTAM, EDTA, HBED/HBED-CC, HYNIC, NODAGA, NODA, NODASA, NOPO, NOTA and PCTA and their derivates.
  • the radionuclides can be administrated in gel, micelle, sphere, particle, microparticle or nanoparticle forms and including therapeutics such as: 166 Ho-Chitosan used for hepatocellular carcinoma treatment (available from Dong Wha.), 90Y-SIR-Spheres a resin-based microspheres used for hepatocellular carcinoma treatment(available from Sirtex), 90Y- TheraSpheres a suspension of insoluble glass microspheres used for transarterial radioembolization in hepatic neoplasia including hepatocellular carcinoma(available from BTG/Boston Scientific), 90Y-RadioGel a hydrogel liquid made of water-based biodegradable polymer that delivers 90Y microspheres directly into tumor tissues (Vivos Inc.), 131 I-SapC-DOPS ( 131 I-Saposin; 131 I-BXD-350) a nanovesicle composed of Saposin C (SapC) coupled to dioleoyl
  • the radionuclides can be conjugated with small molecules (with molecular weight from a hundred to several thousand daltons). These molecules are generally but not limited designed on the basis of natural ligands that have a specific affinity for some receptors that are expressed on the surface of tumors. Natural molecules already used as drugs are often starting points for the development of such tracers and drugs. As a consequence, small molecules have the highest potential to cover all types of indications and including therapeutics such as: 47Sc- cm10 ( 47 Sc-DOTA-Folate, 47 Sc-Folate) a folate analogue cm-10 is a combination of three entities: the folic acid, a DOTA-chelator and an albumin binding.
  • Mechanism of action Folate (Paul Scherrer Institute), 90 Y/ 177 Lu-FAPI-04 and 90 Y/ 177 Lu-FAPI-46 a DOTA-coupled quinolone analogue based on a Fibroblast Activation Protein (FAP)-specific enzyme inhibitor (FAPI).
  • FAP Fibroblast Activation Protein
  • FPI Fibroblast Activation Protein-specific enzyme inhibitor
  • Mechanism of action Alkyl PhosphoCholine (University of Wisconsin-Madison), 117 mSn-RAGE a targeting agent to the receptor against glycation end-products (RAGE) for the treatment of Alzheimer’s disease.
  • Mechanism of action Receptor Against Glycation End-products (NeuroSn, Inc.), 131 I-CLR-131 ( 131 I-CLR-1404, 131 I-NM404, 131 I-18-p-iodophenyl-octadecyl phosphorcholine) an alkyl phosphocholine (APC) from the family of phospholipid ether (PLE) analogs.
  • Mechanism of action (PI3K)/Akt (Cellectar Biosciences), 149 Tb-DOTA-Folate a folate derivate.
  • Mechanism of action Folate receptor (Paul Scherrer Institute), 131 I-IITM ( 131 I-Iodo-N-[4-(6-(isopropylamino)pyridine-4- yl)-1,3-thiazol-2-yl]-N-methyl benzamide) a benzamide targeting the ectopic metabotropic glutamate receptor 1 (mGluR1) used in melanomas.
  • mGluR1 ectopic metabotropic glutamate receptor 1
  • mGluR1 (NIQRST), 131 I-BA52 ( 131 I-benzo(1,3)dioxolo-5-carboxylic acid (4-(2-diethylamino-ethylcarbamoyl)-2-iodo-5- methoxy-phenyl)-amide) a melanin-binding benzamide for the therapy of malignant melanomas.
  • Mechanism of action bisphosphonate (Mainz University / ITM), 177 Lu-FF-10158 an antagonist targeting integrin ⁇ v ⁇ 3 and ⁇ v ⁇ 5 receptors.
  • Mechanism of action GRPR (Johns Hopkins Medical Institutions / NIH), 177 Lu-DO3A-VS- Cys40-Exendin-4 ( 177 Lu-Exendin-4; 177 Lu-DO3A-Exendin-4) a molecule targeting the Glucagon- like peptide-1.
  • Mechanism of action VLA-4 (University of Pittsburgh), 177 Lu-EBRGD ( 177 Lu-EB-RGD; 177 Lu-DOTA-EBRGD) a molecule conjugated with Evans Blue (EB) structure to bind albumin, targeting integrin ⁇ v ⁇ 3 receptor.
  • Mechanism of action Integrin (Molecular Targeting Technologies Inc.), 177 Lu-NM600 ( 177 Lu- DOTA-18-(p-aminophenyl)octadecyl phosphocholine) a tumor-targeting alkylphosphocholine.
  • Mechanism of action alkylphosphocholine (APC).
  • the radionuclides can be conjugated with proteins (such as antibodies, antigen binding fragments, Bispecific Antibodies, affibodies, or Fibronectin type III domains) including therapeutics such as : 67 Cu-CTPA-mAB35 an anti CEA monoclonal antibody, 67Ga- THP-Trastuzumab a mAb targeting HER2 (St.
  • 90 Y-DOTA-FF-21101 90 Y-FF-21101, FF-21101
  • a chimeric monoclonal anti-P-Cadherin (CDH3) mAb (FUJIFILM Pharmaceuticals)
  • 90 Y-OTSA101-DTPA 90 Y-OTSA101, 90 Y-Tabituximab barzuxetan, TT641 pAb, FZD10 mAb) an anti-FZD10 (Frizzled Homolog 10) antibody
  • 90 Y- Clivatuzumab tetraxetan hPAM4-CideTM
  • hPAM4-CideTM 90 Y- Clivatuzumab tetraxetan
  • hPAM4-CideTM 90 Y- Clivatuzumab tetraxetan
  • hPAM4-CideTM 90 Y- Clivatuzumab tetraxetan
  • 90 Y-Ferritarg a rabbit polyclonal antibody which targets Ferritin (Alissa Pharma)
  • 90 Y- IDEC-159 a monoclonal antibody which targets TAG-72
  • 90 Y-IDEC-159 a monoclonal antibody reactive to tumor-associated glycoprotein (TAG-72).
  • Biogen Idec 117mSn-DOTA-Annexin-V a natural protein that can be used to both image and treat vulnerable plaque, cancers or rheumatoid arthritis (Serene LLC), 131 I-Tenatumomab a Tenascin-C targeting monoclonal antibody (ST2146) (Sigma-tau), 131 I-chTNT ( 131 I-chTNT-1/B; 131 I-TNT, Cotara®, Vivatuxin®, 131 I-derlotuximab biotin) a DNA/histone-targeting monoclonal antibody used to treat brain cancer through in situ infusion directly into the tumor.
  • 131 I-Metuximab an antibody fragment targeting the hepatocellular cancer (HCC)-associated antigen HAb18G/CD147.
  • HCC hepatocellular cancer
  • 131 I- Tositumomab Bexxar®
  • an anti-CD20 antibody GaxoSmithKline
  • 131 I-Weimeisheng a chimeric antibody CIRC - Shanghai Meien Biotechnology
  • 131 I-CAM-H2 131 I-SGMIB anti-HER2-VHH1; 131 I-SGMIB
  • sdAb single domain antibody fragment targeting HER2.
  • 131 I-CR3022 an antibody targeting specifically the SARS-CoV-2 RBD (host cell receptor binding domain).
  • MSKCC 131 I-81C6 ( 131 I-Monoclonal Antibody 81C6, 131 I-MoAB 81C6, NeuradiabTM) a murine IgG2 anti-tenascin monoclonal antibody (Bradmer Pharmaceuticals), 131 I-Naxitamab ( 131 I-3F8, 131 I-MoAb-3F8) a murine IgG3 monoclonal antibody which binds to the cell-surface GD2, a disialoganglioside antigen (Y-Mabs Therapeutics), 131 I-Omburtamab ( 131 I-Burtomab, 131 I-8H9; 131 I- 8H9 (B7-H3), 131 I-MoAb-8H9) a murine monoclonal antibody IgG1 recognizing cell surface antigen 4Ig-B7H
  • 131 I Radretumab 131 I-L19-SIP, 131 I-L19SIP
  • ED-B extra-domain B
  • 177 Lu-DTPA- TRC105 an anti-CD105 antibody (Tracon Pharmaceuticals), 177 Lu-225Ac-hu11B6 ( 177 Lu-DTPA- hu11B6; 177 Lu-h11B6) a PSMA targeting antibody (Lund University), 177 Lu-Humalutin ( 177 Lu- NNV003) an anti-CD37 antibody (Nordic Nanovector), 177 Lu/225Ac-Rosapatumab (J591, TLX591) an anti-PSMA (prostate-specific membrane antigen) an antibody with high specificity for prostate tumor cells (Telix Pharmaceuticals), 177 Lu-TLX250 ( 177 Lu-cG250, TLX250, 177 Lu- TLX250t, 177 Lu-Lutarex®, 177 Lu-DOTA-Girentuximab, 177 Lu-Girentuximab) a chimeric murine human monoclonal antibody which targets the Carbonic Anhydras
  • TLX251 225 Ac-Girentuximab (TLX251) a chimeric murine human monoclonal antibody which targets the Carbonic Anhydrase IX (CA-IX) molecule/G250 antigen, expressed on over 90% of clear cell renal cell carcinomas.
  • CA-IX Carbonic Anhydrase IX
  • 225 Ac-J591 225 Ac-ATL-101, 225 Ac-TLX591
  • an anti-PSMA prostate-specific membrane antigen
  • 225 Ac-TLX251 225 Ac-cG250, 225 Ac-DOTA-Girentuximab, 225 Ac-Girentuximab
  • CA-IX Carbonic Anhydrase IX
  • 225 Ac-TLX591 (225Ac-J591) anti-PSMA (prostate-specific membrane antigen) antibody with high specificity for prostate tumor cells (Telix Pharma / Weill Medical College of Cornell University), 225 Ac-TLX592 ( 225 Ac-J591, improved 225 Ac-TLX591 ) a re-engineered antibody hu591 targeting PSMA (Telix Pharma), 225 Ac-FPI-1434 an humanized monoclonal antibody which targets the insulin-like growth factor-1 receptor (IGF-1R) (Fusion Pharmaceuticals), 225 Ac-Lintuzumab ( 225 Ac-Actimab-ATM, 225 Ac-DOTA-huM195, 225 Ac-DOTA-Lintuzumab, 225 Ac-CHX-A’’-DOTA-huM195, Lin-Ac225, 225 Ac- huM195) an anti-CD33 humanized antibody huM195 (Actinium Pharmaceuticals), 225
  • the radionuclides can be conjugated with a peptide or polypeptide including therapeutics such as: somatostatin analogues targeting somatostatin (SST) receptors with for e.g. 90 Y-DOTATATE ( 90 Y-DOTA0- Phe1-Tyr3-octreotate, 90 Y-Octreotate, and 90 Y-DOTA-Octreotate), Lutetium ( 177 Lu)Oxodotreotide [INN] (Lutathera®, 177 Lu-DOTATATE, 177 Lu-DOTA0-Tyr3-octreotate, 177 Lu- Octreotate, 177 Lu-Lutate, 177 Lu-Edotreotate officially USAN: lutetium Lu-177inate and INN: lutetium ( 177 Lu) oxodotreotide) (AAA/Novartis), 213 Bi-DOTATATE ( 213 Bi-[DOTATATE
  • the radioligand agent is selected from any of the agents disclosed in 1) Theranostics 2016; 7(7): 1928-1939, 2) The Journal of Nuclear Medicine, Vol.60, No.7, 910-916, 3) Mol Imaging Biol 2020 April ; 22(2): 274-284, and related electronic supplementary material, all of which are hereby incorporated by reference.
  • the radioligand agent is selected from 177 Lu-CTT1401, 177 Lu-CTT1403, CTT1057 (which incorporates 18F) and 177 Lu- CTT1751. Bombesin analogues targeting Gastrin Releasing Peptide Receptor (GRPR) with for e.g.
  • GRPR Gastrin Releasing Peptide Receptor
  • 177Lu-NeoB ( 177 Lu-NeoBomb1, 177 Lu-DOTA-(p-aminobenzylamine-diglycolic acid)-[D-Phe6- His- NHCH-[(CH2CH(CH3)2]212-des-Leu13-des-Met14] BBN) (Novartis), 177Lu-ProBOMB1 (68Ga- DOTA-pABzA-DIG-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu- ⁇ (CH2N)- Pro-NH2) (University of British Columbia), 212Pb-RM2 (212Pb-DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala- Val-Gly-His-Sta-Leu-NH2) (US Department of Veterans Affairs), 177 Lu-RM2 ( 177 Lu-DOTA-4- amino-1-carboxymethyl-pipe
  • Integrin Radioligands 68 Ga-FF58 ( 68 Ga-2,2’,2’’-(10-(2-(((R)-1-((2-(4-(4-(N-((S)-1-carboxy-2-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentanamide)ethyl)sulfamoyl)-3,5-diemthylphenoxy)butanamide)ethyl)amino)- 1-oxo-3-sulfopropan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) and 177Lu-FF58 (177Lu-2,2’,2’’’-(10-(2-(((R)-1-((2-(4-(4-(N-((S)-1-carboxy-2-
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) that can be used in the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
  • a compound that can be used in the present invention can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Any resulting racemates of compounds that can be used in the present invention or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds that can be used in the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic compounds that can be used in the present or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal PAT059671 former under crystallization conditions and isolating co-crystals thereby formed.
  • suitable co- crystal formers include those described in WO 2004/078163.
  • the compounds that can be used in the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water).
  • solvate refers to a molecular complex of a compound (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • the WRN bifunctional degrader molecule is a compound of Formula Ia: or a pharmaceutically acceptable salt thereof, wherein: the Targeting Ligand is a group that is capable of binding to Werner Syndrome RecQ DNA helicase (WRN), such as a compound of Formula 1g, or Compound A, Compound C, or Compound B herein; the Linker is a group that covalently links the Targeting Ligand to the Targeting Ligase Binder; and the Targeting Ligase Binder is a group that is capable of binding to a ligase (e.g., VHL, IAP or Cereblon E3 Ubiquitin ligase.
  • WRN Werner Syndrome RecQ DNA helicase
  • an antibody-drug conjugate comprising a WRN inhibitor compound as described herein.
  • Antibodies and linker components can be selected according to those known in the art.
  • PAT059671 Methods (Examples 1 to 3, Figs 1 to 10) Experiments were performed in female Crl:NU(NCr)-Foxn1 nu -homozygous nude mice (Charles River) or NOD-Rag2 tm1 -IL2rg tm1 /Rj (NRG) mice (Janvier) or CB17.Cg-PrkcscidLystbg-J/Crl SCID beige (Charles River).
  • the JHUEM-2 cells were cultured in DMEM Ham’s F12 (BioConcept #1-26F08-0I) supplemented with 10% FBS (Corning #35-015-CV), 4mM L-Glutamine (BioConcept # 5-10K50-H) and 1mM Sodium Pyruvate (BioConcept # 5-60F00-H) at 37 ⁇ C in an atmosphere of 5%CO 2 .
  • Both RKO and OVK-18 were cultured in MEM Eagle (BioConcept #1-31S01-I) supplemented with 10% FBS (Corning #35-015-CV), 2mM L-Glutamine (BioConcept # 5-10K50-H) and 1mM Sodium Pyruvate (BioConcept # 5-60F00-H) at 37 ⁇ C in an atmosphere of 5%CO 2 .
  • MEM Eagle BioConcept #1-31S01-I
  • the %T/C value is calculated at the end of the experiment according to: ( ⁇ tumor volume treated / ⁇ tumor volume control )*100 Tumor regression was calculated according to: -( ⁇ tumor volume treated /tumor volume treated at start )*100 PAT059671 Where ⁇ tumor volumes represent the mean tumor volume on the evaluation day minus the mean tumor volume at the start of the experiment. Regression was evaluated after at least seven days of treatment.
  • Example 1 Combination of Compound A with carboplatin and paclitaxel Treatment was initiated about one (OVK18) or two weeks (JHUEM2) post tumor cell inoculation, when the xenografts reached a mean volume of approximately 200 mm 3 .
  • the tumor bearing animals were randomized based on tumor volumes into experimental groups with 6 animals per group and treatment was initiated.
  • Compound A was dosed orally (p.o.) once per day (qd) at 10 mg/kg; carboplatin was dosed intraperitoneally (i.p) once per week either at 25 mg/kg (JHUEM2) or at 50 mg/kg (OVK18); paclitaxel was dosed intravenously (i.v.) once per week at 12.5 mg/kg in both studies.
  • a control group treated once per day orally (p.o.) with vehicle (20% 2-hydroxypropyl- ⁇ -cyclodextrin) was included in each study. Tumor volumes and body weights were measured two times per week until the study termination.
  • Groups treated with Compound A as standalone and with combined carboplatin and paclitaxel displayed minor tumor growth delay compared to vehicle control (eight day of the treatment to reach 550mm3 on average for both groups against fifth day for a vehicle control).
  • Group treated with Compound A on top of carboplatin and paclitaxel maintained stable disease throughout the treatment phase, with maximum regression of 10% reached after ten days of treatment (Figure 1).
  • PAT059671 In the study assessing an efficacy of Compound A in combination with carboplatin and paclitaxel in JHUEM2 model the tumors in the vehicle treated group grew approximately linearly from about 200 to 1.000 mm 3 ( Figure 3). Throughout the treatment duration the vehicle treated animals gained up to 11% of body weight at the treatment start ( Figure 4).
  • Example 2 Combination of Compound A with External Beam Radiotherapy (EBRT) Treatment was initiated about one week post tumor cell inoculation, when the xenografts reached a mean volume of approximately 190 mm 3 (OVK18). The tumor bearing animals were randomized based on tumor volumes into experimental groups with 6 animals per group and treatment was initiated.
  • EBRT External Beam Radiotherapy
  • Compound A was dosed orally (p.o.) once per day (qd) at 10 mg/kg; external beam radiotherapy (EBRT) was applied at 5Gy once per week or at 7.5Gy every other week (OVK18) or at 2.5Gy once per week or at 5Gy every other week (JHUEM2).
  • EBRT external beam radiotherapy
  • a control group treated once per day orally (p.o.) with vehicle (20% 2-hydroxypropyl- ⁇ - cyclodextrin) was included in each study. Tumor volumes and body weights were measured two times per week until the study termination.
  • Example 3 Combination of Compound A with irinotecan Treatment was initiated about one week post tumor cell inoculation, when the xenografts reached a mean volume of approximately 200 mm 3 .
  • the tumor bearing animals were PAT059671 randomized based on tumor volumes into experimental groups with 6 animals per group and treatment was initiated.
  • Compound A was dosed orally (p.o.) once per day (qd) at 3 or 10 mg/kg; irinotecan was dosed intravenously (i.v.) once per week at 15 mg/kg.
  • Efficacy of WRN inhibitors against subcutaneous MSI endometrial patient derived xenografts Methods (Examples 4 and 5, Figs 11 to 26) Experiments were performed in female Crl:NU(NCr)-Foxn1 nu -homozygous nude mice (Charles River). Animals were housed under Optimized Hygienic Conditions in Allentown XJ cages (IVC, max.
  • mice 6 mice per cage) with food and water at libitum and a 12h:12h light: dark cycle. Animals were allowed to acclimatize for at least 1 week before being enrolled in the experimental PAT059671 design. The study described here was performed according to license 1975 approved by the Basel Cantonal Veterinary Office. Four endometrial PDX models were tested: 3200HX (OD33776), 4412HX (OD37223), 20669HX (ND01590), 2781HX (OD32866). The source vendor of the models is the National Disease Research Interchange (NDRI).
  • NDRI National Disease Research Interchange
  • tumor piece of around 3x3mm was put in half DMEM medium (BioConcept #1-26F03-I) and half Matrigel (Corning #354234) for at least 10min and then implanted s.c in the right flank of animals which were anaesthetized with isoflurane.
  • %T/C value is calculated at the end of the experiment according to: ( ⁇ tumor volume treated / ⁇ tumor volume control )*100
  • Tumor regression was calculated according to: -(tumor volume treated /tumor volume treated at start )*100
  • ⁇ tumor volumes represent the mean tumor volume on the evaluation day minus the mean tumor volume at the start of the experiment. Regression was evaluated after at least seven days of treatment.
  • Amorphous sodium salt of test Compound A or Compound C (corrected by salt factor) was dissolved in an aqueous 20% w/v solution of 2-hydroxypropyl-beta-cyclodextrin (HPBCD).
  • Paclitaxel (Sandoz, Pharmacode #4896111) was diluted with 5% glucose solution.
  • Carboplatin (Sandoz, Pharmacode #7209565) was diluted with 0.9% sodium chloride solution.
  • Example 4 Combination of WRN inhibitor Compound A or C, with carboplatin and paclitaxel Treatment was initiated when the xenografts reached a mean volume of approximately 160-180 mm 3 .
  • the tumor bearing animals were randomized based on tumor volumes into experimental groups with 5 or 6 animals per group at start.
  • Group treated with Compound A on top of carboplatin and paclitaxel maintained regression from the second week of the treatment phase, with maximum regression of 97% reached after thirty-seven days of treatment (Figure 11).
  • Group treated with Compound C on top of carboplatin and paclitaxel maintained stable disease throughout the treatment phase, with maximum regression of 40% reached after twenty-eight days of treatment ( Figure 11). After 70 days the treatment with either Compound A or Compound C was discontinued. At this point one tumor out of four or one out of two remaining on the study and treated with either Compound A or Compound C, respectively, on top of carboplatin and paclitaxel was palpable and relapsed after treatment discontinuation.
  • Groups treated with Compound A or Compound C as standalone or with combined carboplatin and paclitaxel displayed tumor growth delay compared to a vehicle control (twenty eighth or fourteenth or seventeenth day of the treatment, respectively, to reach 450mm 3 on average against eighth day for a vehicle control).
  • Group treated with Compound A or Compound C on top of carboplatin and paclitaxel maintained stable disease throughout the treatment phase, with maximum PAT059671 regression of 54% reached after sixty-five days of treatment or 46% reached after forty-eight days of treatment, respectively (Figure 15).
  • Example 5 Combination with EBRT Treatment was initiated when the xenografts reached a mean volume of approximately 140-230 mm 3 .
  • the tumor bearing animals were randomized based on tumor volumes into experimental groups with 5-6 animals per group at start.
  • Groups treated with Compound A or Compound C as standalone did PAT059671 not benefit from the treatment and had no tumor growth delay compared to a vehicle control (seventh or fifth day of the treatment, respectively, to reach 450mm 3 on average against sixth day for a vehicle control).
  • Group treated with EBRT only maintained regression from the second week of the treatment phase, with maximum regression of 76% reached after fifty-five days of treatment ( Figure 21).
  • Groups treated with either Compound A or Compound C on top of EBRT maintained regression from the second week of the treatment phase, with maximum regression of 55% reached after thirty-one days of treatment or of 70% reached after fifty-eight days of treatment, respectively (Figure 21).
  • Group treated with Compound C as standalone showed only minor growth delay compared to vehicle control (eighth day of treatment to reach 450mm 3 on average against fourth day for a vehicle).
  • Group treated with EBRT as standalone displayed strong tumor growth delay compared to a vehicle control (sixteenth day of treatment to reach 450mm 3 on average against fourth day for a vehicle control).
  • Group treated with Compound C on top of EBRT maintained stable disease throughout the treatment phase, with T/C oscillating between 4 and 16% within first 13 days (when control group was available) and reaching 2% regression after twenty-three days of treatment (Figure 23).

Landscapes

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

Abstract

La présente invention concerne des combinaisons pharmaceutiques comprenant un inhibiteur de WRN pour le traitement du cancer, le traitement comprenant en outre l'administration d'une thérapie par rayonnement ionisant choisie parmi un rayonnement de faisceau externe, une curiethérapie et un produit radiopharmaceutique, ou comprenant en outre une combinaison de carboplatine et de paclitaxel.
PCT/IB2025/053691 2024-04-10 2025-04-08 Combinaisons pharmaceutiques et leurs utilisations Pending WO2025215527A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202463632048P 2024-04-10 2024-04-10
US63/632,048 2024-04-10
US202563760236P 2025-02-19 2025-02-19
US63/760,236 2025-02-19

Publications (2)

Publication Number Publication Date
WO2025215527A2 true WO2025215527A2 (fr) 2025-10-16
WO2025215527A3 WO2025215527A3 (fr) 2025-11-20

Family

ID=95519205

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2025/053691 Pending WO2025215527A2 (fr) 2024-04-10 2025-04-08 Combinaisons pharmaceutiques et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2025215527A2 (fr)

Citations (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078163A2 (fr) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a base d'un co-cristal
WO2015107495A1 (fr) 2014-01-17 2015-07-23 Novartis Ag Composés n-hétéroaryle substitués par un n-azaspirocycloalcane et compositions pour inhiber l'activité de shp2
WO2017058716A1 (fr) 2015-09-28 2017-04-06 Vivace Therapeutics, Inc. Composés tricycliques
WO2018204532A1 (fr) 2017-05-03 2018-11-08 Vivace Therapeutics, Inc. Composés tricycliques non fusionnés
WO2019040380A1 (fr) 2017-08-21 2019-02-28 Vivace Therapeutics, Inc. Composés de benzosulfonyle
WO2019113236A1 (fr) 2017-12-06 2019-06-13 Vivace Therapeutics, Inc. Composés benzocarbonyle
WO2019222431A1 (fr) 2018-05-16 2019-11-21 Vivace Therapeutics, Inc. Composés d'oxadiazole
WO2020097389A1 (fr) 2018-11-09 2020-05-14 Vivace Therapeutics, Inc. Composés bicycliques
WO2020214734A1 (fr) 2019-04-16 2020-10-22 Vivace Therapeutics, Inc. Composés bicycliques
WO2020243415A2 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020243423A1 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2021102204A1 (fr) 2019-11-20 2021-05-27 Vivace Therapeutics, Inc. Composés hétéroaryles
WO2021124222A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Dérivés de pyrazolyle utiles en tant qu'agents anticancéreux
WO2021186324A1 (fr) 2020-03-16 2021-09-23 Novartis Ag Dérivés biaryle en tant qu'inhibiteurs d'interaction protéine-protéine yap/taz-tead
WO2022087008A1 (fr) 2020-10-21 2022-04-28 Vivace Therapeutics, Inc. Composés carboxamides tertiaires
WO2022120355A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Agents de dégradation de tead et leurs utilisations
WO2022120353A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2022120354A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et utilisations associées
WO2022159986A1 (fr) 2021-01-25 2022-07-28 Ikena Oncology, Inc. Combinaison d'un inhibiteur de tead de 3-(imidazol-4-yl)-4-(amino)-benzène sulfonamide avec un inhibiteur de l'egfr et/ou un inhibiteur de mek pour une utilisation dans le traitement du cancer du poumon
WO2022249060A1 (fr) 2021-05-26 2022-12-01 Novartis Ag Analogues de triazolo-pyrimidine pour le traitement de maladies liées à l'inhibition de l'hélicase recq du syndrome de werner (wrn)
WO2024079623A1 (fr) 2022-10-12 2024-04-18 Novartis Ag Composés tricycliques et leurs utilisations
WO2024120378A2 (fr) 2022-12-05 2024-06-13 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Composés de triazole, procédés de préparation et utilisations médicinales de ceux-ci
WO2024140714A1 (fr) 2022-12-30 2024-07-04 苏州浦合医药科技有限公司 Inhibiteur de wrn
WO2024140597A1 (fr) 2022-12-30 2024-07-04 苏州浦合医药科技有限公司 Inhibiteur de l'hélicase wrn
WO2024153155A1 (fr) 2023-01-18 2024-07-25 成都微芯药业有限公司 Inhibiteur de wrn double hétérocyclique, son procédé de préparation et son utilisation
WO2024155884A1 (fr) 2023-01-20 2024-07-25 Synnovation Therapeutics, Inc. Composés hétérocycliques en tant qu'inhibiteurs de wrn
WO2024153244A1 (fr) 2023-01-20 2024-07-25 南京再明医药有限公司 Composé contenant de l'azote
WO2024187049A1 (fr) 2023-03-08 2024-09-12 Synnovation Therapeutics, Inc. Composés hétérocycliques en tant qu'inhibiteurs de wrn
CN118684678A (zh) 2023-03-24 2024-09-24 上海济煜医药科技有限公司 一类作为wrn解旋酶抑制剂的化合物及其制备方法
WO2024193683A1 (fr) 2023-03-23 2024-09-26 Danatlas Pharmaceuticals Co., Ltd. Dérivés bicycliques, compositions et utilisations de ceux-ci
WO2024193716A1 (fr) 2023-03-17 2024-09-26 南京再明医药有限公司 Composé de triazolopyrimidine
WO2024199108A1 (fr) 2023-03-24 2024-10-03 上海济煜医药科技有限公司 Composé agissant en tant qu'inhibiteur de l'hélicase wrn
WO2024199109A1 (fr) 2023-03-24 2024-10-03 上海济煜医药科技有限公司 Composé hétérocyclique servant d'inhibiteur d'hélicase wrn, et procédé de préparation et d'utilisation du composé hétérocyclique
WO2024215923A2 (fr) 2023-04-11 2024-10-17 Nimbus Wadjet, Inc. Inhibiteurs de wrn à base de sulfone vinylique cyclique
CN118787645A (zh) 2023-04-11 2024-10-18 中国科学院上海药物研究所 苯基氨基嘧啶化合物在制备wrn抑制剂中的应用
WO2024220887A1 (fr) 2023-04-21 2024-10-24 Nimbus Wadjet, Inc. Inhibiteurs de wrn à base de [1,2,4]triazolo[1,5-a]pyrimidinone
WO2024222842A1 (fr) 2023-04-27 2024-10-31 Danatlas Pharmaceuticals Co., Ltd. Dérivés hétérocycliques tricycliques, compositions et utilisations de ceux-ci
WO2024222866A1 (fr) 2023-04-27 2024-10-31 Danatlas Pharmaceuticals Co., Ltd. Dérivés cycliques, compositions et utilisations de ceux-ci
WO2024222677A1 (fr) 2023-04-25 2024-10-31 苏州浦合医药科技有限公司 Inhibiteur de wrn
WO2024230828A1 (fr) 2023-05-11 2024-11-14 InventisBio Co., Ltd. Composés, procédés de préparation et utilisations de ceux-ci
WO2024235292A1 (fr) 2023-05-17 2024-11-21 Insilico Medicine Ip Limited Dérivés spiro utilisés comme inhibiteurs de wrn
CN118994204A (zh) 2023-05-18 2024-11-22 轩竹生物科技股份有限公司 Wrn抑制剂及其用途
CN119019407A (zh) 2024-03-18 2024-11-26 苏州浦合医药科技有限公司 针对msi-h实体瘤的三氮唑并嘧啶酮小分子wrn抑制剂
CN119039303A (zh) 2024-09-20 2024-11-29 上海信诺维生物医药有限公司 一种螺环化合物
CN119039203A (zh) 2024-09-20 2024-11-29 上海信诺维生物医药有限公司 一类含有马来酰亚胺结构的化合物
CN119039190A (zh) 2024-09-20 2024-11-29 上海信诺维生物医药有限公司 一种wrn抑制剂
CN119039191A (zh) 2024-09-20 2024-11-29 上海信诺维生物医药有限公司 一类含有亚砜结构的化合物
WO2024246862A1 (fr) 2023-06-01 2024-12-05 Glaxosmithkline Intellectual Property (No. 4) Limited Composés chimiques et leurs utilisations
CN119101045A (zh) 2023-06-08 2024-12-10 上海宇道生物技术有限公司 一类含氮杂环类化合物及其制备方法和应用
WO2024254511A2 (fr) 2023-06-08 2024-12-12 Nimbus Wadjet, Inc. Inhibiteurs de wrn
WO2024254602A1 (fr) 2023-06-09 2024-12-12 Nimbus Wadjet, Inc. Inhibiteurs de wrn à base d'oxazolopyridin-7(4h)-one
WO2024259048A2 (fr) 2023-06-13 2024-12-19 Nimbus Wadjet, Inc. Inhibiteurs de thiazolopyridin-7(4h)-one wrn
WO2024255790A1 (fr) 2023-06-15 2024-12-19 勤浩医药（苏州）有限公司 Composés cycliques fusionnés, composition pharmaceutique le comprenant et leur utilisation
WO2024255765A1 (fr) 2023-06-12 2024-12-19 Nuphase Therapeutics (Hangzhou) Limited., Co. Nouveaux composés, compositions les comprenant et leurs utilisations
CN119161363A (zh) 2023-06-19 2024-12-20 南京圣和药业股份有限公司 作为wrn抑制剂的化合物及其应用
WO2025002413A1 (fr) 2023-06-28 2025-01-02 Shanghai Hansoh Biomedical Co., Ltd. Composés azotés aromatiques, procédés de préparation et utilisations médicinales de ceux-ci
WO2025014877A2 (fr) 2023-07-07 2025-01-16 Nimbus Wadjet, Inc. Inhibiteurs triazolo de wrn
WO2025014846A1 (fr) 2023-07-11 2025-01-16 Merck Sharp & Dohme Llc Inhibiteurs d'hélicase wrn spirocycliques
WO2025021148A1 (fr) 2023-07-27 2025-01-30 贝达药业股份有限公司 Inhibiteur de wrn, composition pharmaceutique associée et utilisation associée

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4618991A1 (fr) * 2022-11-18 2025-09-24 Novartis AG Combinaisons pharmaceutiques et leurs utilisations

Patent Citations (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078163A2 (fr) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a base d'un co-cristal
WO2015107495A1 (fr) 2014-01-17 2015-07-23 Novartis Ag Composés n-hétéroaryle substitués par un n-azaspirocycloalcane et compositions pour inhiber l'activité de shp2
WO2017058716A1 (fr) 2015-09-28 2017-04-06 Vivace Therapeutics, Inc. Composés tricycliques
WO2018204532A1 (fr) 2017-05-03 2018-11-08 Vivace Therapeutics, Inc. Composés tricycliques non fusionnés
WO2019040380A1 (fr) 2017-08-21 2019-02-28 Vivace Therapeutics, Inc. Composés de benzosulfonyle
WO2019113236A1 (fr) 2017-12-06 2019-06-13 Vivace Therapeutics, Inc. Composés benzocarbonyle
WO2019222431A1 (fr) 2018-05-16 2019-11-21 Vivace Therapeutics, Inc. Composés d'oxadiazole
WO2020097389A1 (fr) 2018-11-09 2020-05-14 Vivace Therapeutics, Inc. Composés bicycliques
WO2020214734A1 (fr) 2019-04-16 2020-10-22 Vivace Therapeutics, Inc. Composés bicycliques
WO2020243415A2 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020243423A1 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2021102204A1 (fr) 2019-11-20 2021-05-27 Vivace Therapeutics, Inc. Composés hétéroaryles
WO2021124222A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Dérivés de pyrazolyle utiles en tant qu'agents anticancéreux
WO2021186324A1 (fr) 2020-03-16 2021-09-23 Novartis Ag Dérivés biaryle en tant qu'inhibiteurs d'interaction protéine-protéine yap/taz-tead
WO2022087008A1 (fr) 2020-10-21 2022-04-28 Vivace Therapeutics, Inc. Composés carboxamides tertiaires
WO2022120355A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Agents de dégradation de tead et leurs utilisations
WO2022120353A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2022120354A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et utilisations associées
WO2022159986A1 (fr) 2021-01-25 2022-07-28 Ikena Oncology, Inc. Combinaison d'un inhibiteur de tead de 3-(imidazol-4-yl)-4-(amino)-benzène sulfonamide avec un inhibiteur de l'egfr et/ou un inhibiteur de mek pour une utilisation dans le traitement du cancer du poumon
WO2022249060A1 (fr) 2021-05-26 2022-12-01 Novartis Ag Analogues de triazolo-pyrimidine pour le traitement de maladies liées à l'inhibition de l'hélicase recq du syndrome de werner (wrn)
US20230046859A1 (en) 2021-05-26 2023-02-16 Novartis Ag Bicyclic Compounds and their Uses
US20240245694A1 (en) 2022-10-12 2024-07-25 Novartis Ag Tricyclic Compounds and their Uses
WO2024079623A1 (fr) 2022-10-12 2024-04-18 Novartis Ag Composés tricycliques et leurs utilisations
WO2024120378A2 (fr) 2022-12-05 2024-06-13 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Composés de triazole, procédés de préparation et utilisations médicinales de ceux-ci
WO2024140714A1 (fr) 2022-12-30 2024-07-04 苏州浦合医药科技有限公司 Inhibiteur de wrn
WO2024140597A1 (fr) 2022-12-30 2024-07-04 苏州浦合医药科技有限公司 Inhibiteur de l'hélicase wrn
WO2024153155A1 (fr) 2023-01-18 2024-07-25 成都微芯药业有限公司 Inhibiteur de wrn double hétérocyclique, son procédé de préparation et son utilisation
WO2024155884A1 (fr) 2023-01-20 2024-07-25 Synnovation Therapeutics, Inc. Composés hétérocycliques en tant qu'inhibiteurs de wrn
WO2024153244A1 (fr) 2023-01-20 2024-07-25 南京再明医药有限公司 Composé contenant de l'azote
WO2024187049A1 (fr) 2023-03-08 2024-09-12 Synnovation Therapeutics, Inc. Composés hétérocycliques en tant qu'inhibiteurs de wrn
WO2024193716A1 (fr) 2023-03-17 2024-09-26 南京再明医药有限公司 Composé de triazolopyrimidine
WO2024193683A1 (fr) 2023-03-23 2024-09-26 Danatlas Pharmaceuticals Co., Ltd. Dérivés bicycliques, compositions et utilisations de ceux-ci
CN118684678A (zh) 2023-03-24 2024-09-24 上海济煜医药科技有限公司 一类作为wrn解旋酶抑制剂的化合物及其制备方法
WO2024199108A1 (fr) 2023-03-24 2024-10-03 上海济煜医药科技有限公司 Composé agissant en tant qu'inhibiteur de l'hélicase wrn
WO2024199109A1 (fr) 2023-03-24 2024-10-03 上海济煜医药科技有限公司 Composé hétérocyclique servant d'inhibiteur d'hélicase wrn, et procédé de préparation et d'utilisation du composé hétérocyclique
WO2024215923A2 (fr) 2023-04-11 2024-10-17 Nimbus Wadjet, Inc. Inhibiteurs de wrn à base de sulfone vinylique cyclique
CN118787645A (zh) 2023-04-11 2024-10-18 中国科学院上海药物研究所 苯基氨基嘧啶化合物在制备wrn抑制剂中的应用
WO2024220887A1 (fr) 2023-04-21 2024-10-24 Nimbus Wadjet, Inc. Inhibiteurs de wrn à base de [1,2,4]triazolo[1,5-a]pyrimidinone
WO2024222677A1 (fr) 2023-04-25 2024-10-31 苏州浦合医药科技有限公司 Inhibiteur de wrn
WO2024222866A1 (fr) 2023-04-27 2024-10-31 Danatlas Pharmaceuticals Co., Ltd. Dérivés cycliques, compositions et utilisations de ceux-ci
WO2024222842A1 (fr) 2023-04-27 2024-10-31 Danatlas Pharmaceuticals Co., Ltd. Dérivés hétérocycliques tricycliques, compositions et utilisations de ceux-ci
WO2024230828A1 (fr) 2023-05-11 2024-11-14 InventisBio Co., Ltd. Composés, procédés de préparation et utilisations de ceux-ci
WO2024235292A1 (fr) 2023-05-17 2024-11-21 Insilico Medicine Ip Limited Dérivés spiro utilisés comme inhibiteurs de wrn
CN118994204A (zh) 2023-05-18 2024-11-22 轩竹生物科技股份有限公司 Wrn抑制剂及其用途
WO2024246862A1 (fr) 2023-06-01 2024-12-05 Glaxosmithkline Intellectual Property (No. 4) Limited Composés chimiques et leurs utilisations
CN119101045A (zh) 2023-06-08 2024-12-10 上海宇道生物技术有限公司 一类含氮杂环类化合物及其制备方法和应用
US20250034136A1 (en) 2023-06-08 2025-01-30 Nimbus Wadjet, Inc. Wrn inhibitors
WO2024254511A2 (fr) 2023-06-08 2024-12-12 Nimbus Wadjet, Inc. Inhibiteurs de wrn
WO2024254602A1 (fr) 2023-06-09 2024-12-12 Nimbus Wadjet, Inc. Inhibiteurs de wrn à base d'oxazolopyridin-7(4h)-one
WO2024255765A1 (fr) 2023-06-12 2024-12-19 Nuphase Therapeutics (Hangzhou) Limited., Co. Nouveaux composés, compositions les comprenant et leurs utilisations
WO2024259048A2 (fr) 2023-06-13 2024-12-19 Nimbus Wadjet, Inc. Inhibiteurs de thiazolopyridin-7(4h)-one wrn
WO2024255790A1 (fr) 2023-06-15 2024-12-19 勤浩医药（苏州）有限公司 Composés cycliques fusionnés, composition pharmaceutique le comprenant et leur utilisation
CN119161363A (zh) 2023-06-19 2024-12-20 南京圣和药业股份有限公司 作为wrn抑制剂的化合物及其应用
WO2025002413A1 (fr) 2023-06-28 2025-01-02 Shanghai Hansoh Biomedical Co., Ltd. Composés azotés aromatiques, procédés de préparation et utilisations médicinales de ceux-ci
WO2025014877A2 (fr) 2023-07-07 2025-01-16 Nimbus Wadjet, Inc. Inhibiteurs triazolo de wrn
WO2025014846A1 (fr) 2023-07-11 2025-01-16 Merck Sharp & Dohme Llc Inhibiteurs d'hélicase wrn spirocycliques
WO2025021148A1 (fr) 2023-07-27 2025-01-30 贝达药业股份有限公司 Inhibiteur de wrn, composition pharmaceutique associée et utilisation associée
CN119019407A (zh) 2024-03-18 2024-11-26 苏州浦合医药科技有限公司 针对msi-h实体瘤的三氮唑并嘧啶酮小分子wrn抑制剂
CN119039191A (zh) 2024-09-20 2024-11-29 上海信诺维生物医药有限公司 一类含有亚砜结构的化合物
CN119039190A (zh) 2024-09-20 2024-11-29 上海信诺维生物医药有限公司 一种wrn抑制剂
CN119039203A (zh) 2024-09-20 2024-11-29 上海信诺维生物医药有限公司 一类含有马来酰亚胺结构的化合物
CN119039303A (zh) 2024-09-20 2024-11-29 上海信诺维生物医药有限公司 一种螺环化合物

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
"Remington: the Science and Practice of Pharmacy", 2003, AMERICAN PHARMACEUTICALS ASSOCIATION
"Remington's Pharmaceutical Sciences", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
"Uniprot", Database accession no. Q14191
AMODIO ET AL., CANCER CELL, vol. 41, 2023, pages 196 - 209, Retrieved from the Internet <URL:https://doi.org/10.1016/j.ccell.2022.12.003>
BIOCHEMICAL PHARMACOLOGY, vol. 54, 1997, pages 419 - 424
CANCER DISCOV, vol. 12, 2022, pages 1656 - 75
CELL, vol. 177, 2 May 2019 (2019-05-02), pages 821 - 836
CHOU, T.C. AND TALALAY, P., ADV. ENZYME REGUL, vol. 22, 1984, pages 27 - 55
DIETMAIERHOFSTADTER, LAB INVEST, vol. 81, 2001, pages 1453 - 1456
GERMANO, G.LAMBA, S.ROSPO, G ET AL.: "Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth", NATURE, vol. 552, 2017, pages 116 - 120, XP055594122, DOI: 10.1038/nature24673
HOLFORD, N. H. GSCHEINER, L. B., CLIN. PHARMACOKINET, vol. 6, 1981, pages 429 - 453
JOURNAL OF CLINICAL ONCOLOGY, vol. 40, no. 14, 10 May 2022 (2022-05-10), pages 1562 - 1573
KAWAKAMI ET AL., CURR TREAT OPTIONS ONCOL, vol. 16, no. 7, 2015, pages 30
LOEWE, SMUISCHNEK, H., ARCH. EXP. PATHOL PHARMACOL, vol. 114, 1926, pages 313 - 326
MANSOURI AHACHEM LDMANSOURI S ET AL.: "MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges", NEURO ONCOL, vol. 21, no. 2, 2019, pages 167 - 178, XP093088179, DOI: 10.1093/neuonc/noy132
MOL IMAGING BIOL, vol. 22, no. 2, April 2020 (2020-04-01), pages 274 - 284
NAT GENET, vol. 53, no. 7, July 2021 (2021-07-01), pages 1088 - 1096
NATURE, vol. 552, 7 December 2017 (2017-12-07)
RYAN ET AL., CRIT REV ONCOL HEMATOL, vol. 116, 2017, pages 38 - 57
THE JOURNAL OF NUCLEAR MEDICINE, vol. 60, no. 7, pages 910 - 916
THERANOSTICS, vol. 7, no. 7, 2016, pages 1928 - 1939

Also Published As

Publication number Publication date
WO2025215527A3 (fr) 2025-11-20

Similar Documents

Publication Publication Date Title
US20240197715A1 (en) Pharmaceutical combinations and uses thereof
US20250195701A1 (en) Using Targeted Radiotherapy (TRT) to Drive Anti-Tumor Immune Response to Immunotherapies
ES2877629T3 (es) Administración de profármacos activados por hipoxia y agentes antiangiogénicos para el tratamiento del cáncer
CN110536703B (zh) 使用抗axl抗体-药物缀合物的组合疗法
JP2023130496A (ja) 癌治療のための併用療法
AU2018366219B2 (en) Using targeted radiotherapy (TRT) to drive anti-tumor immune response to immunotherapies
WO2021182573A1 (fr) Médicament pour le traitement et/ou la prévention du cancer
JP2024178159A (ja) 癌を治療する方法
CN116744976A (zh) 用于治疗实体癌的her3放射免疫疗法
US20220143228A1 (en) Her3 radioimmunotherapy for the treatment of solid cancers
WO2011112609A1 (fr) Polythérapie pour le traitement du cancer du sein
TW202329936A (zh) 抗體-藥物結合物與parp1選擇性抑制劑之組合
WO2025215527A2 (fr) Combinaisons pharmaceutiques et leurs utilisations
WO2021182571A1 (fr) Médicament pour le traitement et/ou la prévention du cancer
US20250281607A1 (en) Medicament for treatment and/or prevention of cancer
TW202506192A (zh) 抗體-藥物結合物與其他藥劑之組合
WO2021182572A1 (fr) Médicament pour le traitement et/ou la prévention du cancer
CN119744176A (zh) 用于癌的治疗和/或预防的药品
KR20250054778A (ko) 암의 치료 및/또는 예방을 위한 의약품
CN119768181A (zh) 用于癌的治疗和/或预防的药品
EA045355B1 (ru) Комбинированная терапия конъюгатом анти-axl антитело-лекарственное средство