KRAS G12D Modulators Targeting the Active GTP-Bound State

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Solution Overview

Problem

Current therapies for KRAS-driven cancers, particularly those with G12D mutations, are ineffective due to the insensitivity of KRAS G12D to pharmacological targeting, as it has a significantly slower intrinsic rate of GTP hydrolysis, making it difficult to stabilize the inactive GDP-bound state for therapeutic intervention.

Innovation Solution

Development of compounds (Formulas I, II, and III) that selectively inhibit KRAS G12D by binding to the active GTP-bound state, stabilizing a conformation incompetent for oncogenic signaling interactions, thereby inhibiting MAPK signals.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecule inhibitors target the inactive GDP-bound state of KRAS, then covalent modification is achievable through cysteine reactivity, but selective inhibition of KRAS G12D is not achieved due to constitutive activation and slower GTP hydrolysis

Engineering Contradiction:

Improveselective inhibition of KRAS G12DVSAvoidpharmacological targeting of inactive state

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of targeting the inactive GDP-bound state as conventional approaches did, this patent inverts the strategy by designing small molecule inhibitors that selectively bind to and stabilize the active GTP-bound state of KRAS G12D. This inversion allows the drug to trap the mutant protein in a conformation that is incompetent for oncogenic signaling, achieving selective inhibition where previous approaches failed.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent exploits parameter changes in the GTP-bound state conformation, specifically the positioning of switch regions and effector binding interfaces, to create selective inhibition. By targeting parameters such as the spatial arrangement of residues in the active state, the inhibitor achieves selectivity for G12D without affecting normal Ras function in the GDP-bound state.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If small molecule inhibitors bind to the active GTP-bound state of KRAS, then selective inhibition of oncogenic signaling is achieved, but the conformation must be stabilized to be incompetent for effector interactions

Engineering Contradiction:

Improveinhibition of MAPK signals in cancer cellsVSAvoidconformational stability of GTP-bound state

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The inhibitor performs preliminary action by binding to and stabilizing the GTP-bound conformation before oncogenic signaling can occur. By preemptively locking KRAS G12D in a stabilized GTP-bound state with altered switch region positioning, the drug prevents subsequent effector protein interactions and MAPK pathway activation, achieving reliable inhibition of cancer cell proliferation.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If KRAS G12D mutations confer constitutive activation, then tumor progression is driven, but pharmacological targeting becomes resistant

Engineering Contradiction:

Improvedriving of tumor progressionVSAvoidresistance to targeted therapy

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful constitutive activation of KRAS G12D into a therapeutic benefit by exploiting the unique conformational features of the GTP-bound state. The G12D mutation's tendency to remain constitutively active creates a distinct structural signature that the inhibitor recognizes and binds to, transforming the mutation's pathogenic property into a selective vulnerability that can be targeted therapeutically.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS12624052B2KRAS modulators and uses thereof

Publication Date: 2026.05.12 QUANTA THERAPEUTICS INC

AI summary

Provided herein are KRAS modulating compounds, such as compounds of Formula (I), (II) (II*) (III) or pharmaceutically acceptable salts, solvates, stereoisomers, atom labelled, or tautomers of any of the foregoing, useful for modulating KRAS GD12 and/or other G12 mutants.