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Combination therapies

An alkyl and inhibitor technology, which can be used in drug combinations, chemical instruments and methods, active ingredients of heterocyclic compounds, etc., and can solve different problems.

Pending Publication Date: 2021-06-11
MIRATI THERAPEUTICS INC
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Problems solved by technology

[0006] Although the KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzymatic activity and exhibit single agent activity in inhibiting in vitro proliferation of cell lines with the KRas G12C mutation, the relative potency and / or Or the maximal effect observed may vary between KRAS mutant cell lines

Method used

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Examples

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example A

[0265] Pan-ErbB family inhibitors synergistically increase the activity of KRas G12C inhibitors against KRas G12C-expressing cell lines

[0266] This example illustrates exemplary Formula I, Formula I-A, and Formula I-B KRas G12C inhibitor compounds, or pharmaceutically acceptable salts thereof (e.g., compounds selected from Compound Examples Nos. 1-678, or pharmaceutically acceptable salts thereof, For example No. 234, 359, 478 or No. 507 examples or pharmaceutically acceptable salts thereof) and pan-ErbB family inhibitors or pharmaceutically acceptable salts or pharmaceutical compositions thereof synergistically inhibit the growth of tumor cell lines expressing KRas G12C .

[0267]A panel of 9 lung cancer and 1 colorectal cell lines with the KRas G12C mutation was assembled to determine whether combining the pan-ErbB family inhibitors disclosed herein with exemplary KRas G12C inhibitors resulted in synergistic activity. The collection includes NCI-H1373 (ATCC CRL-5866); NCI...

example B

[0284] In vivo model for testing combinations of KRas G12C inhibitors plus pan-ErbB family inhibitors

[0285] The right hind flank of immunocompromised nude mice (nude / nude mice) was inoculated with cells harboring the KRas G12C mutation or patient-derived tumor samples. When the tumor volume reaches 200-400mm 3 When between sizes, mice were divided into four groups of 5-12 mice each. Vehicle only was administered to the first group. Administration of a single agent dose of the KRas G12C inhibitor to the second group at a concentration producing maximal biological effect or a submaximal biological effect did not result in complete tumor regression, depending on the cell line and single agent activity. Administration of a single agent dose of a pan-ErbB inhibitor to a third group at a concentration producing a maximal biological effect or a submaximal biological effect, depending on the cell line and single agent activity, also did not result in complete tumor regression. A...

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Abstract

The present invention relates to combination therapies for treating KRas G12C cancers. In particular, the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a pan ErbB family inhibitor and a KRAS G12C inhibitor of Formula (I), Formula (I-A) or Formula (I-B), pharmaceutical compositions comprising a therapeutically effective amounts of the inhibitors, kits comprising the compositions and methods of use therefor.

Description

technical field [0001] The present invention relates to combination therapies that can be used in the treatment of cancer. Specifically, the present invention relates to therapeutically effective combinations of pan-ErbB family inhibitors and KRas G12C inhibitors, pharmaceutical compositions comprising said inhibitors, kits comprising said compositions and methods of use thereof. Background technique [0002] Kirsten Rat Sarcoma 2 viral oncogene homolog ("KRas") is a member of the small GTPase and Ras oncogene family. KRas acts as a molecular switch cycle between the inactive (GDP-bound) and active (GTP-bound) states to convert upstream cellular signals received from multiple tyrosine kinases into downstream effects that regulate a wide variety of processes including cell proliferation (see, eg, Alamgeer et al., (2013) Current Opin Pharmacol. 13:394-401). [0003] The role of activated KRas in malignant disease was observed more than three decades ago (see, eg, Santos et a...

Claims

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Application Information

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IPC IPC(8): A61K31/18A61K31/44A61K31/4523
CPCA61K45/06A61K31/519A61K31/5377A61K31/517A61K2300/00A61K31/541A61K31/5386A61P35/00C07K16/2863
Inventor 拉尔斯·丹尼尔·恩斯特龙露丝·薇·阿兰达彼得·奥尔森詹姆斯·盖尔·克里斯滕森吉尔·哈林
Owner MIRATI THERAPEUTICS INC
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