Phenol Compound Binding KRAS G12C Mutant Cysteine

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Solution Overview

Problem

Current treatments for KRAS G12C mutant-related cancers, such as pancreatic and lung cancers, lack effective inhibitors that can specifically target and inhibit KRAS G12C mutant activity.

Innovation Solution

Development of a phenol compound represented by Formula (I) that strongly binds to the G12C mutant cysteine of KRAS, inhibiting its activity and providing a pharmaceutical composition for potential therapeutic use.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for KRAS G12C mutant-related cancers, then current standard therapies are administered, but effective inhibition of KRAS G12C mutant activity is not achieved

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidavailability of targeted inhibitors

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent segments the RAS protein family by developing a inhibitor specifically targeted at the KRAS G12C mutant form, distinguishing it from other RAS isoforms (HRAS, NRAS) and wild-type KRAS. This is achieved through selective binding to the cysteine residue at position 12 in the G12C mutant configuration, enabling precise targeting without affecting other RAS proteins.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The phenol compound acts as an intermediary molecule that binds to the cysteine residue of the KRAS G12C mutant, serving as a bridge between the therapeutic goal (inhibiting mutant KRAS) and the molecular target (cysteine thiol group). The compound facilitates inhibition by forming a covalent bond with the cysteine, thereby blocking downstream signaling pathways.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If no specific KRAS G12C inhibitors are available, then alternative cancer treatments must be used, but these do not specifically target the mutant protein

Engineering Contradiction:

Improvespecificity of targeted therapyVSAvoidtherapeutic efficacy

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies local quality by designing a compound with specific functional groups (phenol group, heteroaryl substituent) that are localized to interact with the cysteine residue of KRAS G12C. The molecular structure is optimized with specific substituents (R1, R2, R3, R4, R5, R6, R7, R8) that provide localized interactions with the target protein, ensuring high specificity for the G12C mutant while maintaining therapeutic efficacy.

Inventive Principle:

Principle #3Local quality

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The phenol compound effectively inhibits KRAS G12C mutant activity, offering a novel approach for treating KRAS G12C mutant-related cancers by blocking downstream signaling and inducing apoptosis in cancer cells.

Implementation Method 1

a phenol compound having inhibitory activity against a KRAS G12C mutant... binds to the G12C mutant cysteine of KRAS and inhibits KRAS functions

Methodology Applied

Scientific EffectChemical Bonding: Chemical Bonding

Data Source

PatentUS12479834B2Phenol compound or salt thereof

Publication Date: 2025.11.25 TAIHO PHARMA CO LTD

AI summary

The present invention provides a phenol compound represented by the following Formula (I) or a salt thereof:wherein R1, R2, R5, L1, L2, L3, A, X, and m are as described in the specification.