Matthew L. Condakes, Zhuo Zhang, Derek B. Danahy, Richard R. Moore, Sirish Kaushik Lakkaraju, Xiaoliang Zhuo, Yuka Amako, R. M. Borzilleri, Srividya B. Balachander, Lisa Chourb, Rita L. Civiello, Ashok Dongre, Daniel P. Downes, Dieter M. Drexler, Brianne M. Dudiak, Liudmila Dzhekieva, Miriam El-Samin, Brian E. Fink, Kosea S. Frederick, Cherrie Huang, Javed Khan, Emma Lees, Christopher Levins, Courtney T. McCarthy, Gabriel A. Mintier, Katherine Mosure, Michael F. Parker, Ryan L. Powles, Jie Qi, Max Ruzanov, Sanya Sharma, S. Sheriff, Ashish Kumar Singh, Justin Stedman, Nicolas Szapiel, Rebecca L. Thompson, Wayne Vaccaro, T Wang, Tianfu Yang, Dan You, Matthew J. Meyer, Joanne J. Bronson, Michelle L. Stewart
The discovery of KRAS G12C inactive state inhibitors represented a significant advancement in the field of precision oncology. While inactive state inhibition shows promise in patients, Switch II (SWII)-binding inhibitors targeting both inactive and active states remain an underdeveloped therapeutic modality. Here, we describe the discovery of such KRAS G12C dual inhibitors that bind the SWII allosteric site using a chemically differentiated warhead to covalently modify both the KRAS G12C inactive and active states. Co-crystal structures reveal that these inhibitors perturb a key water-mediated hydrogen bonding network and trigger allosteric remodeling of the GTP-bound protein surface and SWI that prevents binding to downstream effectors. Consistent with simultaneous targeting of the active and inactive states, dual inhibitors provide rapid covalent target engagement and suppression of MAPK signaling. However, they demonstrate similar efficacy in cellular and in vivo models when compared to inactive state-selective ones despite faster target inactivation. Furthermore, both inhibitor classes show similar cellular efficacy in the presence of growth factors that drive KRAS, wt NRAS, and wt HRAS to the active state. These data provide the first detailed account of targeting both the active and inactive states of KRAS G12C and highlight the absence of a mechanistic advantage in contexts dependent on prolonged target inhibition. KRAS is an oncogene that switches between a GDP-bound inactive state and a GTP-bound active state. Recently developed KRAS G12C inhibitors are specific to the GDP-bound inactive state. Here, the authors develop a class of covalent KRAS G12C inhibitors capable of targeting both states for the treatment of KRAS-driven cancer.