Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy

  • J Med Chem. 2025 Aug 14;68(15):15649-15668. doi: 10.1021/acs.jmedchem.5c00576.
Joachim Bröker  1 ,  Alex G Waterson  2 ,  Timothy R Hodges  2 ,  Jason R Abbott  2 ,  Allison Arnold  2 ,  Jark Böttcher  1 ,  Nina Braun  1 ,  Jianwen Cui  2 ,  Julian E Fuchs  1 ,  Thomas Gerstberger  1 ,  Sebastian Gogg  1 ,  Sabine Hanner  1 ,  Lorenz Herdeis  1 ,  Lucas W Howell  2 ,  Andreas Mantoulidis  1 ,  Moriz Mayer  1 ,  Jason Phan  2 ,  Francesca Rocchetti  1 ,  Kyra Sankar  1 ,  Dhruba Sarkar  2 ,  Otmar Schaaf  1 ,  John L Sensintaffar  2 ,  Qi Sun  2 ,  Tobias Wunberg  1 ,  Stephen W Fesik  2
Affiliations
  • 1. Boehringer Ingelheim RCV GmbH & Co., KG, Dr. Boehringer Gasse 5-11, A-1121 Vienna, Austria.
  • 2. Vanderbilt University School of Medicine, Department of Biochemistry, 2215 Garland Ave., 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
PMID: 40709733 DOI: 10.1021/acs.jmedchem.5c00576
Abstract

KRAS is one of the most highly validated Cancer targets. Here we describe the design and synthesis of two reversible pan-KRAS inhibitors, BI-2865 and BI-2493. From our KRASG12C inhibitor program, we identified BI-2865, a potent noncovalent KRAS inhibitor that showed cellular activity against a broad spectrum of KRAS alleles and selectivity against HRAS and NRAS. Spirocyclization led to the discovery of BI-2493, a highly rigid analogue exhibiting better potency, metabolic stability, and permeability. BI-2493 shows in vivo efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models and represents a promising starting point for further optimization.

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