Substituted Pyrido[4,3-d]Pyrimidines for KRAS Codon 12 Inhibition
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Solution Overview
Problem
There is an unmet need to identify and develop novel compounds for KRAS inhibition, as KRAS was previously considered un-targetable, but recent studies have shown that targeting codon 12 can lead to therapeutic effects.
Innovation Solution
Development of substituted pyrido[4,3-d]pyrimidines as KRAS inhibitors, which are compounds with specific structural features that can inhibit KRAS protein activity in both in vitro and in vivo settings.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If KRAS is targeted at codon 12, then therapeutic effects are achieved, but previously KRAS was considered un-targetable
Solution Approach 1:
The patent applies local quality by designing compounds that specifically target the codon 12 region of KRAS protein. The substituted pyrido[4,3-d]pyrimidine structure is engineered to interact with specific amino acid residues at codon 12, creating localized binding affinity that overcomes the previously un-targetable nature of this region while maintaining selectivity and therapeutic efficacy.
2Adaptability or versatility
If substituted pyrido[4,3-d]pyrimidines are developed as KRAS inhibitors, then novel therapeutic compounds are identified, but compound structure complexity increases
Solution Approach 1:
The patent employs segmentation by dividing the KRAS binding interface into distinct regions that can be targeted by specific substituents on the pyrido[4,3-d]pyrimidine core. Different substituents at positions X1, X2, X3, and R1-R4 can independently interact with different regions of the KRAS protein, allowing the compound to be segmented into functional modules that can be optimized separately for binding affinity and selectivity.
Solution Approach 2:
The patent uses composite materials by combining the pyrido[4,3-d]pyrimidine core structure with various heterocyclic substituents (such as pyridine, pyrimidine, triazine rings) and alkyl/alkenyl groups. This composite molecular architecture integrates multiple functional elements that work synergistically to achieve high-affinity binding to KRAS at codon 12, overcoming the complexity challenge through rational molecular design.
Data Source
AI summary
Provided herein are inhibitors of KRAS, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the KRAS inhibitory compounds for the treatment of diseases or disorders.