KRAS G12C Inhibitor Compounds for Resistant Cancer Treatment
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, particularly those with KRAS mutations, as existing therapies are ineffective against KRAS mutations and confer resistance to EGFR targeted therapies.
Innovation Solution
Development of compounds that inhibit the KRAS G12C protein, which can be administered to patients to treat various cancers, including lung cancer, pancreatic cancer, and colorectal cancer, either alone or in combination with other pharmaceutically active compounds such as carfilzomib, venetoclax, daratumumab, or MCI-1 inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapies are used for KRAS mutation-positive cancers, then treatment is provided, but the therapies are ineffective and confer resistance to EGFR targeted therapies
Solution Approach 1:
The patent applies parameter changes by developing compounds with specific molecular structures (Formula 1 and Formula 2) that target the unique conformational state of mutant KRAS proteins. The compounds are designed to bind to specific pockets in the KRAS protein structure that are created or exposed by mutations such as G12C, thereby changing the binding parameters to achieve selective inhibition of mutant KRAS while sparing wild-type KRAS.
Solution Approach 2:
The patent employs local quality by designing inhibitors that specifically target local structural features created by KRAS mutations. The compounds are engineered to recognize and bind to mutation-specific structural alterations in the KRAS protein, such as the cysteine residue at position 12 in G12C mutations, allowing selective inhibition of the mutant form while maintaining normal function of wild-type KRAS.
2Reliability
If new compounds are developed to inhibit KRAS G12C, then treatment efficacy is improved, but device complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the inhibitor molecule into distinct functional modules as shown in Formula 1 and Formula 2. The compounds contain specific structural elements (such as the core heterocyclic ring system, substituent groups R1-R6, and linker regions) that can be independently optimized and synthesized, allowing for modular drug design and simplified manufacturing processes.
Data Source
AI summary
Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.