KRAS G12C–Aurora A Inhibitor Combinations to Overcome Treatment Bypass
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Solution Overview
Problem
There is a need for more potent, orally deliverable combinations of KRAS G12C and Aurora A inhibitors that exhibit synergistic antiproliferative and antitumor effects, while overcoming bypass of KRAS inhibition treatment and minimizing undesired effects, to effectively treat cancers with KRas G12C mutant proteins.
Innovation Solution
Administering a combination of KRAS G12C inhibitors and Aurora A inhibitors, represented by specific compounds of Formulae I-VI or Examples 1-8, in simultaneous, separate, or sequential combinations, to patients with cancer cells expressing KRas G12C mutant proteins, potentially with Aurora A dysregulation or overexpression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If KRAS G12C inhibitors are used alone, then antitumor activity is achieved, but treatment bypass and resistance develop
Solution Approach 1:
The patent combines KRAS G12C inhibitors with Aurora A inhibitors to create a synergistic treatment approach. This combination targets multiple signaling pathways simultaneously, preventing treatment bypass and resistance development while maintaining antitumor activity. The dual inhibition strategy addresses the limitation of single-agent therapy by attacking cancer cells through multiple mechanisms.
Solution Approach 2:
The invention creates a composite therapeutic approach by integrating two different inhibitor classes (KRAS G12C inhibitors and Aurora A inhibitors). This composite strategy leverages the complementary mechanisms of action of both inhibitors to achieve enhanced antitumor effects and overcome resistance pathways that would develop with single-agent therapy.
2Productivity
If combination of KRAS G12C and Aurora A inhibitors is administered, then synergistic antiproliferative effect is achieved, but treatment complexity increases
Solution Approach 1:
The patent merges KRAS G12C inhibitors and Aurora A inhibitors into a unified treatment protocol that achieves synergistic antiproliferative effects. By combining these two inhibitor classes, the treatment targets both KRAS signaling and Aurora A kinase activity, resulting in enhanced cancer cell death while managing treatment complexity through coordinated administration.
3Ease of operation
If single-agent inhibition is used, then treatment simplicity is maintained, but antitumor efficacy is insufficient
Solution Approach 1:
The invention merges two inhibitor therapies to achieve superior antitumor efficacy while maintaining reasonable treatment simplicity. The combination of KRAS G12C inhibitors and Aurora A inhibitors provides enhanced cancer cell killing compared to single-agent therapy, with the added benefit of preventing resistance and treatment bypass.
Data Source
AI summary
The present disclosure provides method of treating a patient for cancer wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof, effective amounts of a compound of the formula:where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, B, and Y are as described herein, or pharmaceutically acceptable salts thereof, and an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof.