Abstract: KRAS is one of the most frequently mutated oncogenes in human cancer.  Despite more than three decades of research, indirect approaches targeting KRAS-mutant cancers have largely failed to show clinical benefit, and direct approaches have been stymied by the apparently ‘undruggable’ nature of KRAS.  I’ll describe efforts at Amgen to identify cysteine-reactive molecules capable of selectively inhibiting a prevalent KRAS mutation, KRASG12C.  These efforts leveraged iterative screening and structural biology studies, property-based optimization, and careful process engineering to ultimately deliver a highly potent, selective, and well-tolerated inhibitor of KRASG12C: LUMAKRAS® (sotorasib).