泛KRAS抑制剂BI-2493的发现及其疗效

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

作者信息

Bröker Joachim, Waterson Alex G, Hodges Timothy R, Abbott Jason R, Arnold Allison, Böttcher Jark, Braun Nina, Cui Jianwen, Fuchs Julian E, Gerstberger Thomas, Gogg Sebastian, Hanner Sabine, Herdeis Lorenz, Howell Lucas W, Mantoulidis Andreas, Mayer Moriz, Phan Jason, Rocchetti Francesca, Sankar Kyra, Sarkar Dhruba, Schaaf Otmar, Sensintaffar John L, Sun Qi, Wunberg Tobias, Fesik Stephen W

机构信息

Boehringer Ingelheim RCV GmbH & Co., KG, Dr. Boehringer Gasse 5-11, A-1121 Vienna, Austria.

Vanderbilt University School of Medicine, Department of Biochemistry, 2215 Garland Ave., 607 Light Hall, Nashville, Tennessee 37232-0146, United States.

出版信息

J Med Chem. 2025 Aug 14;68(15):15649-15668. doi: 10.1021/acs.jmedchem.5c00576. Epub 2025 Jul 25.

DOI:10.1021/acs.jmedchem.5c00576

PMID:40709733

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12362595/

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 KRAS 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 efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models and represents a promising starting point for further optimization.

摘要

KRAS是最经过充分验证的癌症靶点之一。在此，我们描述了两种可逆性泛KRAS抑制剂BI-2865和BI-2493的设计与合成。从我们的KRAS抑制剂项目中，我们鉴定出了BI-2865，一种强效非共价KRAS抑制剂，它对多种KRAS等位基因显示出细胞活性，并对HRAS和NRAS具有选择性。螺环化导致了BI-2493的发现，这是一种高度刚性的类似物，具有更好的效力、代谢稳定性和通透性。BI-2493在各种KRAS突变型和KRAS野生型扩增异种移植模型中均显示出疗效，是进一步优化的一个有前景的起点。