2. Academic Validation
  3. Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162960
    99.93%, pan-KRAS Inhibitor
    Ras