KRAS G12D Modulators That Stabilize a Signaling-Incompetent State

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Solution Overview

Problem

Current therapies for KRAS G12D-driven cancers are ineffective due to the insensitivity of KRAS G12D mutations to existing targeted therapies, as they confer a significantly slower intrinsic rate of GTP hydrolysis, making it difficult to pharmacologically target the inactive state, and there is a need for inhibitors that selectively bind to the active GTP-bound state to inhibit MAPK signaling.

Innovation Solution

Development of a compound represented by Formula (I) or its pharmaceutically acceptable salts, which selectively bind to the active GTP-bound state of KRAS G12D, stabilizing a conformation incompetent for oncogenic signaling interactions with effector proteins, thereby inhibiting MAPK signals.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If covalent modification with small molecule inhibitors is used to trap KRAS in the inactive GDP-bound state, then KRAS G12C mutations show clinical susceptibility, but KRAS G12D mutations remain resistant due to slower intrinsic rate of GTP hydrolysis

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmutant specificity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the binding state parameter from GDP-bound (inactive) to GTP-bound (active) state targeting. By designing inhibitors that selectively bind to the GTP-bound state and stabilize an incompetent conformation, the therapy becomes effective against KRAS G12D mutations which have slower GTP hydrolysis rates, while maintaining selectivity through state-specific binding rather than mutation-specific covalent modification.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If inhibitors bind to the inactive GDP-bound state, then covalent modification is achieved, but selective inhibition of cancer cells with normal Ras function is difficult

Engineering Contradiction:

Improveinhibition effectivenessVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

Instead of targeting the inactive GDP-bound state as conventional inhibitors do, the patent inverts the approach by targeting the active GTP-bound state. This inversion allows selective inhibition of cancer cells with mutant KRAS that are constitutively active, while sparing normal cells with wild-type Ras that properly cycle between active and inactive states, thereby reducing off-target effects.

Inventive Principle:

Principle #13The other way round (Inversion)

3Adaptability or versatility

If KRAS is targeted in the active GTP-bound state, then selective inhibition of MAPK signaling is achieved, but development of effective inhibitors is challenging

Engineering Contradiction:

ImproveselectivityVSAvoidinhibitor development

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent employs a non-covalent binding mechanism as an intermediary approach between the inhibitor and KRAS. By using a binding pocket that accommodates the GTP-bound state conformation and stabilizes an incompetent state through non-covalent interactions, the inhibitor achieves selective inhibition without requiring the challenging covalent modification chemistry that has limited success against KRAS G12D mutations.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20260008789A1KRAS modulators and uses thereof

Publication Date: 2026.01.08 QUANTA THERAPEUTICS INC

AI summary

Provided herein are KRAS modulating compounds, such as compounds of Formula (I), (I-A), (I-B), (I-C), (I-C*), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), or pharmaceutically acceptable salts, solvates, stereoisomers, atom labelled, or tautomers of any one thereof. The compounds provided herein are useful for modulating KRAS G12D and/or other G12 mutants.