Eli Lilly Advances Novel KRAS G12C Inhibitor LY3537982 into Clinical Development

KRAS is one of the most frequently mutated oncogenes in human cancers. In addition to directly promoting tumor cell proliferation and survival, KRAS mutations can also influence the tumor microenvironment. Due to the lack of surface “pockets” capable of binding small-molecule drugs, the KRAS protein has historically been regarded as a notorious “undruggable” target. However, drug development targeting KRAS mutants has achieved breakthroughs in recent years. Small-molecule inhibitors directed against the KRAS G12C mutant, developed by Amgen and Mirati Therapeutics, have entered pivotal clinical development. Notably, Amgen’s KRAS G12C inhibitor has received Priority Review designation from the U.S. Food and Drug Administration (FDA) and is expected to be approved this year.

Eli Lilly and Company recently announced that it will present preclinical results of its next-generation KRAS G12C-specific inhibitor, LY3537982, at the AACR Annual Meeting in April this year. Based on positive preclinical findings, the company plans to initiate Phase 1 clinical trials this year to evaluate the safety and potential efficacy of this candidate drug.

The abstract published by the AACR demonstrated that this selective KRAS G12C inhibitor exhibited robust activity in vitro. KRAS activation requires binding to GTP. By binding to the KRAS G12C mutant, the KRAS G12C inhibitor locks KRAS in a GDP-bound state, thereby inhibiting KRAS signaling. In lung cancer cell lines harboring the KRAS G12C mutation, LY3537982 inhibited KRAS–GTP binding with an IC50 of 3.35 nM. In multiple murine tumor models bearing KRAS G12C genetic alterations, LY3537982 significantly suppressed tumor proliferation or induced complete tumor regression.

Preclinical studies have also found that combining certain targeted therapies with LY3537982 may produce better anti-cancer effects, including the specific AurA inhibitor LY3295668 and the EGFR inhibitor cetuximab.

Researchers have demonstrated that this potent KRAS G12C inhibitor is expected to nearly completely suppress KRAS protein activation, thereby potentially providing maximal clinical benefit to patients harboring the KRAS G12C genetic variant.

Note: This article is intended to introduce medical and health research and does not constitute a recommendation for treatment plans. For guidance on treatment options, please consult a licensed healthcare provider at a reputable hospital.

References:

[1] Lilly rejoins KRAS race with swipe at Amgen and Mirati, plans 2021 clinical trial. Retrieved March 11, 2021 from https://www.fiercebiotech.com/biotech/lilly-rejoins-kras-race-swipe-at-amgen-and-mirati-plans-2021-clinical-trial

[2] 1259 - Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor. Retrieved March 11, 2021, from https://www.abstractsonline.com/pp8/#!/9325/presentation/2344

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