KRAS G12C Acid Salts and Crystal Forms for Stable Inhibition
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current KRAS G12C inhibitors face challenges in development due to the smooth structure of the RAS protein, difficulty in binding small molecules, and high affinity of RAS GTPase for GTP, limiting their effectiveness and availability as targeted cancer treatments.
Innovation Solution
Development of specific acid salts and crystal forms of nitrogen-containing heterocyclic derivatives, such as pyridazine derivatives, to enhance the selectivity, activity, and safety of KRAS G12C inhibitors, facilitating easier processing, storage, and improved bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule drugs are used to target KRAS G12C, then direct KRAS inhibition is achieved, but the smooth structure of RAS protein makes binding difficult
Solution Approach 1:
The patent exploits the local structural change created by the G12C mutation, which generates a unique hydrophobic pocket and altered conformation in the Switch II region. The inhibitor is designed to specifically bind to this mutated local structure rather than the overall smooth RAS surface, achieving selective binding to KRAS G12C while avoiding the general binding difficulty posed by the protein's smooth structure
Solution Approach 2:
The patent employs a covalent warhead (electrophilic group) as an intermediary that forms a covalent bond with the cysteine residue at position 12. This covalent interaction serves as a mediator that overcomes the difficulty of binding to the smooth RAS surface by creating a direct, irreversible chemical linkage between the inhibitor and the mutated protein
2Reliability
If small molecule drugs are used to block RAS-GTP interaction, then KRAS activation is inhibited, but the high affinity of RAS GTPase for GTP and high endogenous GTP levels make blocking difficult
Solution Approach 1:
The patent employs a covalent warhead that irreversibly modifies the cysteine residue at position 12 before GTP can bind to activate KRAS. This preliminary covalent binding locks the protein in its inactive GDP-bound conformation, preventing subsequent GTP binding and activation. The covalent modification occurs first, establishing a permanent block that overcomes the competitive challenge posed by high endogenous GTP levels
Solution Approach 2:
The patent converts the high affinity of RAS for GTP, which normally makes inhibition difficult, into a benefit by designing an irreversible covalent inhibitor that permanently traps KRAS in its inactive state. The strong binding affinity that usually favors GTP binding is redirected toward the covalent inhibitor, which forms an even stronger irreversible bond that cannot be displaced by endogenous GTP
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
A salt and a crystal form relating to a nitrogen-containing heterocyclic derivative, a preparation method therefor and an application thereof. In particular, the present invention relates to a salt and crystal form of a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition comprising a therapeutically effective amount of the crystal form, and a use thereof as a KRAS G12C mutation inhibitor in the treatment of diseases or conditions such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer and colon cancer. Each substituent in the general formula (I) is the same as defined in the description.