Macrocycle Compounds for KRAS Resistance and Allele Coverage
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapies for KRAS mutant cancers, particularly those driven by KRAS G12C mutations, face challenges with acquired resistance and the lack of effective treatments for the majority of KRAS-mutated or wild-type amplified cancers, necessitating the development of novel compounds that inhibit KRAS alleles to prevent resistance mechanisms.
Innovation Solution
Development of novel macrocycle compounds, including specific organic compounds of formula (I) and their pharmaceutically acceptable salts, which target and inhibit KRAS G12C, G12D, and G12V mutations, demonstrating superior cancer cell inhibition, human hepatocyte stability, and improved pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If first generation KRAS G12C inhibitors like Sotorosib and Adagrasib are used, then initial treatment efficacy is improved, but acquired resistance emerges rigorously with disease progression
Solution Approach 1:
The patent applies preliminary action by designing macrocycle compounds that preemptively target multiple KRAS alleles and resistance mechanisms before they can develop. The compounds are structured to bind to KRAS in its active GTP-bound state, preventing activation of downstream signaling pathways that would otherwise lead to resistance. This proactive approach addresses the contradiction by establishing therapeutic effectiveness before resistance can emerge, rather than reacting to resistance after it develops.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure of KRAS inhibitors to create macrocycle compounds with distinct binding characteristics. These macrocycles change the pharmacological parameters by binding to different conformational states of KRAS and utilizing different binding pockets, thereby altering the mechanism of action to overcome resistance mechanisms that have developed against first-generation inhibitors.
2Measurement precision
If KRAS inhibitors are developed to target specific mutations like G12C, then treatment specificity is improved, but effectiveness for majority of KRAS-mutated cancers (including G12D, G12V, and wild-type amplified) remains limited
Solution Approach 1:
The patent applies universality by designing macrocycle compounds that can target multiple KRAS alleles (G12C, G12D, G12V) and wild-type amplified forms through a single molecular framework. The compounds exhibit broad specificity by binding to conserved structural features across different KRAS variants, enabling one inhibitor to address multiple mutation types and genetic alterations simultaneously, thereby resolving the contradiction between specificity and versatility.
Solution Approach 2:
The patent employs segmentation by dividing the KRAS protein structure into distinct functional regions (switch I, switch II, P-loop) and designing macrocycle compounds that can interact with different segments depending on the specific KRAS variant. This allows the inhibitor to adapt its binding mode to match the structural characteristics of different KRAS alleles, achieving broad coverage while maintaining high affinity for each variant.
3Reliability
If existing KRAS inhibitors are used, then cancer cell inhibition is achieved, but solubility and pharmacokinetic properties need improvement
Solution Approach 1:
The patent applies composite materials by creating macrocycle compounds that integrate multiple functional moieties within a single molecular structure. These macrocycles combine hydrophilic and hydrophobic regions, along with specific pharmacological groups, to achieve both potent cancer cell inhibition and improved solubility. The composite structure allows the compound to interact effectively with KRAS while maintaining favorable pharmacokinetic properties, resolving the contradiction between biological activity and manufacturability.
Data Source
AI summary
The present invention relates to compounds of formula (I),wherein R1 to R7, A1 and A2 are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.