Combination therapy involving diaryl macrocyclic compounds
Inventors
Deng, Wei • Zhai, Dayong • RODON, Laura • Murray, Brion W. • CUI, Jingrong J. • LEE, Nathan V.
Assignees
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Publication Number
US-11666574-B2
Publication Date
2023-06-06
Expiration Date
Abstract
The present disclosure relates to methods and compositions for treating cancer with a diaryl macrocycle in combination with an inhibitor of MAPK/ERK kinase-1 and -2 (MEK1 and MEK2; MAP2K1 and MAP2K2), such as trametinib.
Core Innovation
The invention concerns a method of treating cancer in a patient in need of such treatment by administering a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 in combination with a therapeutically effective amount of a MEK inhibitor. The MEK inhibitor is trametinib, selumetinib, LY3214996, RO5126766, TNO155 (SHP099), or mirdametinib, or a pharmaceutically acceptable salt thereof. The compound is provided as a multi-target small-molecule inhibitor of FAK, SRC and/or JAK2, including an embodiment referred to as Compound 1 defined by structure and general formula(s).
The invention addresses cancer treatment by combining the FAK/SRC/JAK2 inhibitor activity with a MEK1/2 inhibitory agent, including embodiments for co-formulation or same-time versus sequential administration. The description further provides that the MEK inhibitor and the FAK/SRC/JAK2 inhibitor are administered in combination. Cancer types associated with KRAS are enumerated, and the document includes KRAS mutation sets and contexts such as prior treatment and resistance.
The disclosed treatment is directed to cancers including non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic cancer. The description includes embodiments using diarlyl macrocyclic compounds in combination with a MEK1/MEK2 inhibitor, including structural formula embodiments such as Compound 1 and Formula I. Patient and tumor genetic context is addressed by referring to tumors harboring genetically altered oncogenic genes, with emphasis on KRAS mutation sets.
Claims Coverage
The coverage is grounded in one independent claim directed to treating cancer with a FAK/SRC/JAK2 inhibitor administered in combination with a MEK inhibitor. The dependent claims refine the inventive concept by specifying timing, dosing/scheduling, patient treatment history, and cancer context including genetically altered oncogenic genes.
Trivalent FAK/SRC/JAK2 inhibition with MEK inhibition selected from specified MEK inhibitors
Administering to the patient a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 in combination with a therapeutically effective amount of a MEK inhibitor, wherein the MEK inhibitor is trametinib, selumetinib, LY3214996, RO5126766, TNO155 (SHP099), or mirdametinib, or a pharmaceutically acceptable salt thereof.
Specific timing relationship: same time co-administration
Administering the compound that inhibits FAK, SRC, and JAK2 at the same time as a MEK inhibitor.
MEK inhibitor restriction to trametinib
Using the MEK inhibitor trametinib, or a pharmaceutically acceptable salt of trametinib.
Prior chemo/immunotherapy with acquired and/or bypass resistance
Applying the method to a patient who has previously received chemotherapy and/or immunotherapy and has developed acquired and/or bypass resistance to that treatment.
KRAS-defined patient/tumor genetics via specified mutation sets
The genetically altered KRAS includes specified point mutations in certain listed sets, or includes at least one KRAS mutation outside a specified subset.
Across the independent claim and its refinements, the central claimed coverage is combination cancer treatment using a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 together with a therapeutically effective MEK inhibitor selected from a defined list, including trametinib as an example. Dependent claim coverage further constrains co-administration timing, MEK inhibitor selection, prior treatment status with acquired and/or bypass resistance, and tumor genetics via specified KRAS mutation sets.
Stated Advantages
Substantial supporting results for the combination, including synergy and pharmacodynamic and pathway modulation readouts.
Reported outcomes include cell viability effects and apoptosis-associated markers such as caspase-3/7 and PARP cleavage.
Signaling modulation includes kinase phosphorylation readouts such as phospho-ERK, phospho-AKT, phospho-FAK, phospho-SRC, and phospho-STAT3.
Efficacy observations are reported in xenograft models and in patient-derived organoid/spheroid models.
Documented Applications
Treating non-small cell lung cancer (NSCLC).
Treating colorectal cancer.
Treating pancreatic cancer.
Treating cancers in patients having genetically altered oncogenic genes, including KRAS/NRAS/HRAS/BRAF/MEK/PI3K, with emphasis on specific KRAS mutation sets.
Treating patients previously treated with chemotherapy and/or immunotherapy who have acquired and/or bypass resistance to that treatment.
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