Combination therapy involving diaryl macrocyclic compounds
Inventors
Deng, Wei • Zhai, Dayong • RODON, Laura • Murray, Brion W. • CUI, Jingrong J.
Assignees
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Publication Number
US-11654145-B2
Publication Date
2023-05-23
Expiration Date
Abstract
The present disclosure relates to methods and compositions for treating cancer with a diaryl macrocycle in combination with a KRAS inhibitor, such as an inhibitor of KRAS G12C.
Core Innovation
The disclosure provides a method for treating a cancer having a KRAS G12C mutation in a human patient by administering a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C. The compound is defined by a structure and may be administered as a pharmaceutically acceptable salt. The treated cancer is colorectal cancer, pancreatic cancer, or lung cancer.
The KRAS G12C inhibitor used in combination is AMG-510, MRTX849, or ARS-1620, or a pharmaceutically acceptable salt thereof. The compound that inhibits FAK, SRC, and JAK2 can be administered at the same time as, before, or after the KRAS G12C inhibitor. The combination is presented in the context of therapeutic response, synergistic response concepts, and resistance, including intrinsic, acquired, and bypass resistance.
The disclosure further includes pharmaceutical compositions and co-formulated composition concepts for the combined administration. Additional refinements include decreasing IL-6 secretion from the cancer and use in patients who have previously received at least one prior treatment involving chemotherapeutic agents and/or immunotherapies.
Claims Coverage
Two independent method claims are present, directed to treating KRAS G12C-mutant cancers using a therapeutically effective combination of a FAK/SRC/JAK2 inhibitor compound with an agent that inhibits KRAS G12C. The main inventive features are the dual-targeting combination, the KRAS G12C inhibitor options, and the restricted cancer types, with refinements for timing, IL-6 secretion, and prior treatment history.
Combination of a FAK/SRC/JAK2 inhibitor with a KRAS G12C inhibitor
Administering a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, wherein the compound has the structure or a pharmaceutically acceptable salt thereof.
KRAS G12C inhibitor options
The at least one agent that inhibits KRAS G12C is AMG-510, MRTX849, or ARS-1620, or a pharmaceutically acceptable salt thereof.
Cancer types limited to colorectal, pancreatic, or lung cancer
The cancer is colorectal cancer, pancreatic cancer, or lung cancer.
Relative administration timing of the two agents
Administering a compound that inhibits FAK, SRC, and JAK2 at the same time as, before, or after an agent that inhibits KRAS G12C.
IL-6 secretion reduction from the cancer
Decreasing IL-6 secretion from the cancer.
Prior treatment history with chemotherapeutic agents and/or immunotherapies
Providing a method for a human patient who has previously received at least one prior treatment involving chemotherapeutic agents and/or immunotherapies.
Across the independent claims, the core coverage is a KRAS G12C-mutant cancer treatment method combining a compound that inhibits FAK, SRC, and JAK2 with a KRAS G12C inhibitor selected from AMG-510, MRTX849, or ARS-1620, or pharmaceutically acceptable salts, limited to colorectal, pancreatic, or lung cancer. Dependent refinements further cover timing of administration, decreasing IL-6 secretion, and patient selection based on prior chemotherapeutic and/or immunotherapy treatment.
Stated Advantages
Overcomes intrinsic and acquired resistance to KRAS G12C inhibitors, including bypass resistance, via dual/tri-kinase inhibition of FAK/SRC/JAK2 together with KRAS G12C inhibition.
Decreases IL-6 secretion from the cancer.
Documented Applications
Treating KRAS G12C-mutant colorectal cancer in a human patient using a FAK/SRC/JAK2-inhibiting compound in combination with a KRAS G12C inhibitor.
Treating KRAS G12C-mutant pancreatic cancer in a human patient using a FAK/SRC/JAK2-inhibiting compound in combination with a KRAS G12C inhibitor.
Treating KRAS G12C-mutant lung cancer in a human patient using a FAK/SRC/JAK2-inhibiting compound in combination with a KRAS G12C inhibitor.
Using decreased IL-6 secretion from the cancer as a biomarker-linked outcome in the treatment method.
Synergistic compositions combining the FAK/SRC/JAK2 inhibitor with a KRAS G12C inhibitor where the two components contact at a locus, including contexts involving prior-treatment and acquired resistance or bypass-acquired resistance.
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