Fused Ring KRAS Inhibitors for Noncovalent Mutant Selectivity

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Solution Overview

Problem

There is an unmet medical need for noncovalent KRAS inhibitors that can selectively target KRAS mutants such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, and KRAS G13D with good in vivo efficacy, safety, and predicted human oral pharmacokinetic profile for treating patients with KRAS mutant cancers, as existing inhibitors face challenges with bioavailability and lack of tractable binding pockets.

Innovation Solution

Development of fused ring compounds with specific structural features, including heterocycloalkyl and heteroaryl rings, which can selectively target KRAS mutants through noncovalent interactions, potentially improving bioavailability and efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If covalent chemical modifiers (sotorasib and adagrasib) are used to target KRAS G12C, then inhibition efficacy is achieved, but the approach is limited to specific mutants and requires covalent bond formation which may reduce selectivity and increase toxicity

Engineering Contradiction:

Improveinhibition efficacyVSAvoidmutant selectivity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the chemical interaction parameter from covalent bonding to noncovalent binding, allowing the inhibitor to maintain efficacy while gaining versatility across multiple KRAS mutant types without the limitations of covalent modification

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The fused ring compound is designed to universally target multiple KRAS mutant variants (G12C, G12D, G12V, G12R, G12S, G13C, G13D) through a single noncovalent binding mechanism, making the inhibitor multi-functional across different mutant types

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Reliability

If MRTX1133 is administered via intraperitoneal injection to achieve sufficient plasma exposure, then drug efficacy is demonstrated in mice, but bioavailability is poor and route of administration is limited

Engineering Contradiction:

Improvedrug efficacyVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent modifies the chemical structure parameters of the inhibitor to improve pharmacokinetic properties, specifically enhancing oral bioavailability and enabling convenient oral administration while maintaining in vivo efficacy

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If KRAS inhibitors are designed to target multiple mutant variants, then versatility is improved, but the lack of tractable binding pockets makes selective binding difficult

Engineering Contradiction:

Improvemutant coverageVSAvoidbinding pocket accessibility

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent applies local quality by designing the fused ring compound to interact with specific local features of the KRAS switch II pocket, enabling selective binding to multiple mutant variants through targeted interactions with conserved residues in the binding pocket

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20260008787A1Fused ring KRAS inhibitors for treating disease

Publication Date: 2026.01.08 BLOSSOMHILL THERAPEUTICS INC

AI summary

The present disclosure relates to fused ring compounds targeting KRAS, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat disease, such as cancer.