Pan-KRAS Inhibitor Compounds for Active and Inactive KRAS Binding
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Solution Overview
Problem
Current KRAS inhibitors, such as covalent KRAS G12C inhibitors, are limited in effectiveness against the inactive (GDP-bound) form of KRAS and fail to target the active (GTP-bound) form, leading to drug resistance and inability to treat a large population of non-G12C KRAS cancers, highlighting the need for pan-KRAS inhibitors that can target various KRAS mutations and conformations.
Innovation Solution
Development of compounds capable of inhibiting both active and inactive conformations of KRAS proteins with mutations like G12D, G12V, G12C, G12S, G12R, G13D, and Q61H, as well as wild-type KRAS, providing therapeutic advantages over inhibitors targeting only the inactive form.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If covalent KRAS G12C inhibitors (AMG510, MRTX849) are used to target inactive GDP-bound KRAS, then clinical activity is achieved in NSCLC, but effectiveness is reduced against active GTP-bound KRAS and non-G12C mutations leading to drug resistance
Solution Approach 1:
The patent applies universality by designing a single inhibitor compound capable of binding to multiple KRAS mutation types (G12C, G12D, G12V, G13D, Q61L) and both conformational states (GDP-bound and GTP-bound). This multi-functional approach allows one drug to address diverse KRAS-driven cancers that previously required mutation-specific treatments, directly resolving the limitation of G12C-specific inhibitors.
Solution Approach 2:
The patent employs dynamics by creating an inhibitor that can adapt to bind both the inactive GDP-bound state and the active GTP-bound state of KRAS. This dynamic binding capability allows the drug to remain effective regardless of the nucleotide state or specific mutation, preventing resistance development through conformational adaptation rather than targeting a single static state.
2Measurement precision
If KRAS inhibitors target only the inactive GDP-bound form, then specific binding is achieved, but drug resistance develops due to inability to suppress active GTP-bound form
Solution Approach 1:
The patent implements continuity of useful action by designing an inhibitor that maintains therapeutic effect across both GDP-bound and GTP-bound states. Rather than acting only when KRAS is in the inactive state, the compound continues to inhibit KRAS signaling regardless of nucleotide binding status, ensuring continuous suppression of oncogenic signaling and preventing resistance through sustained inhibition.
3Adaptability or versatility
If pan-KRAS inhibitors are developed to target multiple mutations, then coverage of non-G12C cancers is improved, but selectivity and off-target effects become concerns
Solution Approach 1:
The patent applies local quality by designing the inhibitor to recognize specific local features of the KRAS binding pocket that are conserved across different mutations (G12C, G12D, G12V, G13D, Q61L) while maintaining selectivity. The compound targets localized structural characteristics of mutant KRAS proteins rather than broadly interacting with all RAS family members, achieving broad mutation coverage with controlled selectivity.
Data Source
AI summary
Provided herein are compounds, or salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers thereof, as well as pharmaceutical compositions comprising the same. Also provided herein are methods of using the same in modulating (e g., inhibiting) KRAS (e.g., KRAS having a Q61H, G12D, G12V, G12C, G12S, G12A, G12R, or G13D mutation or wild-type KRAS) and treating diseases or disorders such as cancers in subjects in need thereof.