Pyrido[4,3-d]Pyrimidine KRAS Inhibitors Through Scaffold Segmentation
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Solution Overview
Problem
There is an unmet need to identify and develop novel compounds for KRAS inhibition, as KRAS protein 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]pyrimidine compounds as KRAS inhibitors, which are used in pharmaceutical compositions to treat cancer and neoplastic diseases, targeting specific heterocyclyl substituents and optionally substituted aryl or heteroaryl ring systems to inhibit KRAS protein activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If KRAS protein is targeted for therapeutic effect, then cancer treatment efficacy is improved, but previously KRAS was considered un-targetable making development difficult
Solution Approach 1:
The patent modifies the chemical structure of pyrido[4,3-d]pyrimidine compounds by changing parameters such as substituting hydrogen atoms at specific positions (X1, X2, X3) with different groups (N, C-CN, C-H, C-F, C-CH3, C-Cl, C-alkyl, C-alkenyl, C-carbocyclyl), adjusting the heterocyclyl substituents (azabicyclo, oxazabicyclo, diazabicyclo structures), and modifying aryl/heteroaryl ring systems. These structural parameter changes enable the compounds to effectively target KRAS protein while maintaining synthesizability through established organic chemistry methods.
Solution Approach 2:
The patent divides the KRAS inhibitor molecule into distinct functional segments: a core pyrido[4,3-d]pyrimidine scaffold, variable heterocyclyl substituents (azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, oxazabicyclo[4.1.0]heptane, etc.), and aryl/heteroaryl groups. This segmentation allows independent optimization of each component to achieve KRAS inhibition while maintaining manageable synthesis complexity.
2Reliability
If multiple heterocyclyl substituents are incorporated to enhance KRAS inhibition, then therapeutic effectiveness is improved, but molecular complexity increases
Solution Approach 1:
The patent applies local quality by placing specific heterocyclyl substituents at defined positions (X1, X2, X3) on the pyrido[4,3-d]pyrimidine core. Each position has specific requirements: X1 can be N or C-CN, X2 can be N or various carbon-based groups, and X3 can be N or various carbon-based groups. This localized approach ensures KRAS inhibition while controlling overall molecular complexity through systematic substitution patterns.
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.