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Identification of Novel pan-KRAS Inhibitors via Structure-Based Drug Design, Scaffold Hopping, and Biological

Vladimir Aladinskiy¹, Alexey B Mantsyzov¹, Chris Kruse¹

¹Insilico Medicine AI Ltd., Level 6, Unit 08, Block A, IRENA HQ Building, Masdar City, Abu Dhabi, United Arab Emirates, 145748.

ACS Medicinal Chemistry Letters

|July 16, 2025

Abstract:

KRAS is one of the most frequently mutated oncogenes in human cancers. Discovery of the allosteric binding sites next to the switch II loop triggered the successful development of KRAS-targeting therapeutic agents featuring different modalities. pan-KRAS inhibitors are of particular interest due to the broader scope of clinical indications and potential to overcome certain types of emerging resistance typical of allele-specific KRAS modulators. Herein, we explore the chemical space around MRTX1133, a compound with selectivity toward the KRAS^G12D variant, aiming to find new chemotypes with the potential to derive a clinical candidate. A series of novel pan-KRAS inhibitors with a potency in the upper nanomolar range have been developed. The inhibitory activity was demonstrated against key oncogenic KRAS mutants and a wild-type protein.

Insights

Researchers developed novel pan-KRAS inhibitors targeting key cancer mutations. These new compounds show potential for broader clinical use and overcoming resistance to existing KRAS-targeting therapies.

Area of Science:

Oncology
Medicinal Chemistry
Molecular Biology

Background:

KRAS is a frequently mutated oncogene driving human cancers.
Targeting KRAS has led to successful therapeutic agents, but allele-specific inhibitors face resistance.
Pan-KRAS inhibitors offer broader indications and potential to overcome resistance.

Purpose of the Study:

To explore chemical space around MRTX1133 to discover novel chemotypes.
To identify new pan-KRAS inhibitors with potential as clinical candidates.
To develop compounds effective against oncogenic KRAS mutants and wild-type KRAS.

Main Methods:

Exploration of chemical space around MRTX1133.
Synthesis and evaluation of novel pan-KRAS inhibitors.
In vitro assays to determine inhibitory activity against KRAS mutants and wild-type protein.

Main Results:

A series of novel pan-KRAS inhibitors were developed.
Compounds demonstrated potency in the upper nanomolar range.
Inhibitory activity confirmed against key oncogenic KRAS mutants and wild-type KRAS.

Conclusions:

Novel pan-KRAS inhibitors have been successfully developed.
These compounds show promise for broader clinical application in KRAS-driven cancers.
The developed inhibitors may overcome resistance mechanisms associated with allele-specific KRAS modulators.

Read full analysis

Keywords:

KRAS SBDD pan-KRAS pan-RAS scaffold hopping

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