Carlos Stahlhut, Anna E. Maciag, Kyle A. Sullivan, Kanchan Singh, Nadege Gitego, Zuhui Zhang, Albert H. Chan, Alok K. Sharma, Patrick Alexander, Jin Shu, YUE YANG, Megan Rigby, Roger Ma, Saman Setoodeh, Brian P. Smith, Jun Pei, Dana Rabara, Erik K. Larsen, David M. Turner, Cathy Zhang, Cindy Feng, Siyu Feng, James P. Stice, Rui Xu, Ken Lin, Andrew G. Stephen, Felice C. Lightstone, Chunmei Ji, Keshi Wang, Dhirendra K. Simanshu, Dwight V. Nissley, Eli Wallace, Bin Wang, Kerstin W. Sinkevicius, Frank McCormick, PEDRO J. BELTRAN
Although KRASG12C-specific inhibitors have been introduced, no approved targeted therapies exist for other clinically significant KRAS mutants, including KRASG12D and KRASG12V. We discovered BBO-11818, a potent, selective, orally bioavailable noncovalent pan-KRAS inhibitor capable of targeting multiple KRAS mutants in both the inactive GDP-bound (OFF) and active GTP-bound (ON) states. BBO-11818 binds in the Switch-II/Helix 3 pocket, inducing conformational changes incompatible with effector binding, and demonstrates high-affinity binding to mutant KRAS with strong selectivity over NRAS and HRAS. BBO-11818 potently inhibited MAPK signaling and cellular viability specifically in KRAS-driven lines and produced tumor regressions in KRAS-mutant xenograft models. Combination studies with anti-PD-1, anti-EGFR antibodies, and a RAS:PI3Kα breaker compound showed enhanced efficacy. BBO-11818 has entered phase I clinical trials for patients with various KRAS mutations in colorectal, pancreatic, and lung cancers (NCT06917079). SIGNIFICANCE: We discovered BBO-11818, a potent and selective noncovalent KRAS inhibitor with activity against multiple KRAS mutants in both the active (ON) and inactive (OFF) states. BBO-11818 addresses the need for KRAS inhibitors targeting clinically relevant mutants such as KRASG12D and KRASG12V, either as monotherapy or in combination.