KRAS G12D Inhibitors That Lock the Inactive GDP-Bound State

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Solution Overview

Problem

Existing treatments are ineffective against KRAS G12D mutations, which are prevalent in various cancers, as KRAS was considered undruggable due to its stability and lack of targetable states.

Innovation Solution

Development of specific compounds of Formula (I) that selectively inhibit KRAS G12D protein activity by binding to the aspartic acid at position 12, preventing the conversion from inactive GDP to active GTP and inhibiting downstream signaling.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used, then general cancer treatment is provided, but they are ineffective against KRAS G12D mutations

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidmutation specificity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The compound is designed to specifically target the local structural feature of the G12D mutation (aspartic acid at position 12) rather than acting on general RAS protein structures. This localized targeting approach allows the inhibitor to distinguish between mutant and wild-type KRAS, providing mutation-specific treatment effectiveness.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention changes the binding parameters of the inhibitor to match the altered surface properties of the G12D mutant. By adjusting the molecular structure to recognize the specific electrostatic and steric properties introduced by the D12 mutation, the compound achieves high affinity binding only to the mutant form, resolving the contradiction between general effectiveness and mutation specificity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If KRAS is targeted, then cancer signaling is inhibited, but KRAS was considered undruggable due to stability and lack of targetable states

Engineering Contradiction:

ImprovetargetabilityVSAvoidprotein stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The compound exploits the preliminary structural state of KRAS in the GDP-bound inactive conformation. By designing the inhibitor to specifically recognize and bind to this pre-existing state, the drug can intercept KRAS before it transitions to the active GTP-bound state, effectively targeting the protein despite its overall stability and lack of traditional druggable pockets.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention introduces an intermediary molecular structure that bridges the gap between the stable KRAS protein and the desired inhibitory effect. The compound acts as a mediator that binds to the inactive state, stabilizing it and preventing conformational changes necessary for activation, thereby making the stable protein druggable through indirect interference.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentEP4139299B1KRAS g12d protein inhibitors

Publication Date: 2025.12.17 TAIHO PHARMA CO LTD

AI summary

Compounds and pharmaceutically acceptable salts thereof inhibit the G12D mutant of KRAS protein and are expected to have utility as therapeutic agents, for example, for the treatment of cancer.