KRAS G12D Inhibitors Selective Binding Oral Bioavailability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapeutic options for targeting KRas mutations in cancer are limited, with a need for more potent, orally deliverable, and selectively inhibiting KRas GTP activity, especially for KRas G12D mutants, while minimizing side effects and enhancing pharmacokinetic/pharmacodynamic properties.
Innovation Solution
Development of novel KRas inhibitors, specifically compounds of Formula I, which are designed to selectively inhibit KRas G12D mutants over wild-type KRas, and are formulated for oral administration to treat various cancers, including lung, pancreatic, and colorectal cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional KRas inhibitors are used, then KRas G12C mutants can be inhibited, but selectivity against KRas G12D mutants is insufficient and side effects increase
Solution Approach 1:
The compound is designed with specific local chemical features (substituents at positions R1, R2, R3b, R3c, R4, R5, R5a, R6, R7, R8) that create selective interactions with the KRas G12D mutant binding pocket, achieving localized specificity that reduces off-target effects while maintaining inhibition efficacy
Solution Approach 2:
The invention optimizes multiple molecular parameters including steric bulk, electronic properties, and hydrophobicity of substituent groups to fine-tune the compound's binding affinity for KRas G12D while reducing affinity for wild-type KRas and other mutants, thereby improving selectivity and reducing side effects
2Reliability
If KRas inhibitors are designed for high potency, then oral deliverability may be compromised due to pharmacokinetic limitations
Solution Approach 1:
The compound's pharmacokinetic parameters are optimized by adjusting molecular weight, lipophilicity (logP), and hydrogen bonding capacity of the substituent groups, enabling the molecule to achieve both high potency and adequate oral bioavailability by balancing these competing requirements
Solution Approach 2:
The inhibitor combines multiple functional moieties within a single molecular framework, integrating high-affinity binding elements with pharmacokinetic optimization elements, creating a composite structure that simultaneously achieves potency and oral deliverability
3Reliability
If broad-spectrum KRas inhibition is achieved, then selectivity for KRas G12D mutant over wild-type KRas is reduced
Solution Approach 1:
The compound incorporates specific substituent patterns that create local steric and electronic environments complementary to the KRas G12D mutant conformation, enabling selective binding that distinguishes the mutant from wild-type KRas while maintaining coverage of the G12D mutation
Data Source
AI summary
The present invention provides compounds of the formula:wherein A, Z, G, R1, R2, and R4 are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients for cancer.