molecules of the month

Why is the pan-KRAS inhibitor, BI-2493, a big deal? The RAS proteins, KRAS4A, KRAS4B, HRAS, and NRAS control diverse cellular processes, and gain-of-function mutations in RAS genes are found in ~25% of cancers in humans, with KRAS mutations accounting for up to 85% of RAS mutations across cancers. While KRAS(G12C) has been successfully targeted by approved drugs sotorasib and adagrasib and numerous candidates (e.g. BI-0474, AZD4625, JDQ443, ASP2453, ‘compound 25’), it is only the most common KRAS mutation in NSCLC (41% of NSCLC KRAS mutations) – the majority of KRAS mutations observed across cancers involve other mutants. Boehringer Ingelheim recently disclosed a pair of pan-KRAS inhibitors in Nature (BI-2865 and in vivo tool BI-2493, derived from previously disclosed covalent molecule…