Stopping cancer in its tracks: the discovery of a new pan-KRAS inhibitor

Posted by daviskd2 on Thursday, October 16, 2025 in News.

By Cameron I. Cohen

KRAS is an enzyme which, when active, binds effector proteins and results in the activation of downstream pathways involved in cell proliferation, differentiation, and survival. Activating KRAS mutations are therefore common in many cancers, including cancers of the lung, colon, and pancreas, and are the most frequent drivers of malignancy. KRAS belongs to the Ras family of GTPases which cycle between GDP-bound (inactive) and GTP-bound states, the regulation of which is controlled by GEF and GAP proteins. Small molecules have been developed which specifically target KRAS or block binding to GEFs in an effort to reduce aberrant KRAS activity. However, the wide range of KRAS mutations across cancers and the possible development of resistance has resulted in a need for better pan-KRAS inhibitors. Researchers from the Fesik Lab tackle this issue through the design and characterization of two new pan-KRAS inhibitors: BI-2865 and BI-2493.

A series of candidate molecules was first identified through the use of an NMR-based fragment discovery program. Co-crystallization of the various compounds in complex with GDP-KRAS and cell proliferation assays were then used to optimize the structure-function features of candidate compounds. Two molecules, BI-2865 and its spirocyclized analogue BI-2493, emerged as potent, reversible inhibitors of KRAS. Both compounds resulted in decreased proliferation when administered to cells expressing WT KRAS, as well as cells expressing a wide series of different KRAS mutations. Additionally, the antiproliferative effect is observed most strongly in cells expressing KRAS as opposed to cells expressing HRAS and NRAS, other Ras family member proteins, demonstrating the specificity of both compounds for KRAS. However, BI-2493 displayed better potency, metabolic stability, and permeability, as compared to BI-2865, making it the clear choice for continued study.

The authors then sought to determine the in vivo antitumor activity of BI-2493 by orally administering the compound to xenografted mouse models expressing KRAS^G12V or KRAS^G12C. In the KRAS^G12V mouse model, administration of BI-2493 resulted in dose-dependent tumor growth inhibition without causing body weight loss. KRAS^G12C mice also exhibited a drop in tumor growth rate without weight loss upon BI-2493 administration, demonstrating the ability of this compound to inhibit KRAS activity without notable toxicity. BI-2493 is therefore an exciting new pan-KRAS inhibitor which provides the groundwork for the optimization of more potent inhibitors or even the production of proteolysis targeting chimeras (PROTACs), which would result in the degradation of KRAS mutants.

Be sure to check out the full paper in the Journal of Medicinal Chemistry and learn more about the fight against KRAS mutants!

More information

Read this SOMBS news article to learn how the Fesik lab and collaborators are taking other research into clinical trials in the fight against cancer.