KRAS G12C Inhibitor Compounds for GDP- and GTP-Bound Suppression

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current KRAS G12C inhibitors primarily target the GDP-bound form of the protein, leading to resistance through increased GTP-bound KRAS signaling, necessitating compounds that can inhibit both GDP- and GTP-bound forms to effectively treat cancers characterized by the KRAS G12C mutation.

Innovation Solution

Development of compounds, including Formula (I) and Formula (II), which can bind to and inhibit both the inactive GDP- and activated GTP-bound forms of KRAS G12C, offering improved inhibition of the GTP-bound form.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If current KRAS G12C inhibitors (AMG 510, MRTX849) are used to target GDP-bound KRAS, then inhibition of GDP-bound form is achieved with high selectivity (1000-fold preference), but resistance develops rapidly through increased GTP-bound KRAS signaling

Engineering Contradiction:

Improveselectivity for GDP-bound formVSAvoiddurability of treatment response

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent applies universality by designing a single inhibitor compound that can bind to and inhibit both GDP-bound and GTP-bound forms of KRAS G12C. This multi-functional approach allows the drug to address multiple states of the target protein, preventing resistance mechanisms that rely on shifting between GDP and GTP bound states, thereby improving treatment durability while maintaining selectivity

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Adaptability or versatility

If cancer cells increase signaling through RTKs to boost GTP-bound KRAS levels, then resistance to current inhibitors arises, but this creates an opportunity to target GTP-bound form directly

Engineering Contradiction:

Improveability to target both GDP- and GTP-bound formsVSAvoidmolecular design complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of the inhibitor to alter its binding parameters. Specifically, the compound is designed with structural features that enable it to recognize and bind to both GDP-bound and GTP-bound conformations of KRAS G12C, changing the binding affinity parameters to accommodate both states while maintaining sufficient selectivity and potency

Inventive Principle:

Principle #35Parameter changes

3Productivity

If inhibitors bind preferentially to GDP-bound form (1000-fold preference), then initial treatment response is achieved, but response duration is limited and resistance arises rapidly

Engineering Contradiction:

Improveinitial treatment response efficacyVSAvoidduration of treatment response

Core Design Contradiction:

ProductivityVSDuration of action of moving object

Solution Approach 1:

The patent applies continuity of useful action by creating an inhibitor that maintains active inhibition across both GDP-bound and GTP-bound states of KRAS G12C. This continuous inhibition prevents the protein from switching between active and inactive states, ensuring sustained therapeutic effect and preventing the emergence of resistance over time, thereby extending treatment response duration

Inventive Principle:

Principle #20Continuity of useful action

Data Source

PatentUS20250340548A1KRAS g12c inhibitors

Publication Date: 2025.11.06 FRONTIER MEDICINES CORP

AI summary

The present disclosure provides compounds and methods useful in the treatment and suppression of cancer, for example, useful for treating or suppressing cancers characterized by KRAS G12C. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.