molecules of the month

Context. BI-0474 (Boehringer Ingelheim) is a covalent KRASG12C inhibitor. KRAS continues to be a hotly pursued oncotarget since the first report by the Shokat group of the druggability of the KRASG12C mutant. Recently, Amgen’s first-in-class sotorasib (Lumakras) was approved, while Mirati Therapeutics’ adagrasib (MRTX84) may be approved in December 2022, based on its PDUFA date. For BI-0474, Boehringer Ingelheim scientists started with a reversible switch II pocket binder and optimized affinity of the reversible molecule via structure-based design before introducing an acrylamide covalent warhead as a last step. While BI-0474 is a non-oral tool molecule, Boehringer Ingelheim mentions an advanced, orally bioavailable compound from the series (BI 1823911) is currently in early clinical development. Opportunities for differentiation could be better…