KRAS-G12C is an important oncogenic mutation in patients with NSCLC, CRC, and other cancer types. Currently, there are no FDA-approved KRAS-G12C inhibitors, and those in clinical development have relatively modest activity compared to other approved therapies targeting other classic oncogenic drivers. This modest activity may be potentially due in part to incomplete target occupancy and trapping of mutant KRAS in the inactive GDP-bound state. Achieving maximal clinical benefit in patients harboring a KRAS-G12C mutation, may require a potent inhibitor capable of achieving near complete target engagement. Here, we report the identification of LY3537982, a novel, highly selective and potent inhibitor of the KRAS-G12C protein, discovered using structure-based design. In kinetic studies, LY3537982 showed a high Kinact/Ki value (248,016 M-1 s-1), compared to AMG510 (7,220 M-1 s-1) and MRTX849 (35,000 M-1 s-1). LY3537982 inhibited KRAS-GTP loading with an IC50 value of 3.35 nM in the KRAS-G12C mutant H358 lung cancer cell line, while AMG510 and MRTX849 had IC50 values of 47.9 nM and 89.9 nM, respectively. LY3537982 also inhibited phospho-ERK in H358 cells with an IC50 value of 0.65 nM, while the IC50 values of AMG510 and MRTX849 were 13.5 nM and 14 nM, respectively. In a panel of cancer cell lines with KRAS-G12C or non-G12C mutations, LY3537982 selectively inhibited the growth of KRAS-G12C mutant tumor cells and not KRAS wild-type or non-G12C mutant cells. Sensitivity to LY3537982 varied among the KRAS-G12C mutant cells tested, suggesting that not all cell lines maintain the same dependence on KRAS-G12C. Similarly, in multiple xenograft or patient-derived xenograft (PDX) models harboring a KRAS-G12C mutation, LY3537982 exhibited a range of anti-tumor activity from complete regression to significant tumor growth inhibition, at 3 to 30 mg/kg QD or BID. Mechanism-based combinational screens have also identified certain targeted therapies that can synergize with LY3537982 to achieve better anti-tumor activity in vitro and in vivo, including abemaciclib, the selective AurA inhibitor LY3295668, and cetuximab. Together these data suggest that in certain biologic contexts, broader and more durable anti-tumor activity could be achieved with combination regimens. A first-in-human Phase 1 clinical trial is planned for 2021. Citation Format: Sheng-Bin Peng, Chong Si, Youyan Zhang, Robert D. Van Horn, Xi Lin, Xueqian Gong, Lysiane Huber, Gregory Donoho, Carmen Curtis, John M. Strelow, Wayne P. Bocchinfuso, Deqi Guo, Serge L. Boulet, David Barda, Danalyn Manglicmot, Melbert-Brian D. Saflor, Jing Wang, Junpeng Xiao, Michael J. Chalmers, Lee Burns, Ryan J. Linder, Bradley L. Ackermann, Paul D. Cornwell, Lian Zhou, Denis McCann, James Henry. Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1259.