Abstract 4378: BBO-11818, an orally bioavailable, highly potent and non-covalent pan-KRAS inhibitor demonstrates robust anti-tumor activity in KRAS-mutant preclinical models

Abstract KRAS is the most commonly mutated oncogene, altered in approximately 15% of human cancers. While inhibitors of KRASG12C have shown promising clinical efficacy, there are currently no approved targeted therapies against other KRAS variants, resulting in a significant underserved patient population across several major cancer types, including pancreatic carcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). To address this unmet clinical need, we have developed BBO-11818: a potent, selective, orally bioavailable non-covalent pan-KRAS inhibitor with activity against multiple KRAS mutants, including KRASG12D and KRASG12V, in both their inactive GDP-bound and active GTP-bound states. BBO-11818 binds mutant KRAS with high affinity and selectivity in its active and inactive conformations, locking it in the inactive State 1 to disrupt the association of GTP-bound KRAS with its key effector RAF1. Cell-based assays confirm that BBO-11818 potently inhibits several driver KRAS mutants, resulting in the suppression of MAPK signaling and inhibition of cell proliferation with low nanomolar EC50 values. The selectivity of BBO-11818 for KRAS is demonstrated by its >1000-fold lower potency against NRAS- and BRAF-mutant cell lines. BBO-11818 exhibits favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties in mouse models of cancer. Single dose, oral administration results in strong dose- and time-dependent inhibition of pERK in KRASG12D and KRASG12V cell-derived xenograft (CDX) models. Importantly, BBO-11818 monotherapy induces strong anti-tumor responses, including regression at well-tolerated doses in CDX models of KRAS-mutant pancreatic, non-small cell lung, and colorectal cancer. In combination with either BBO-10203, a selective RAS:PI3Kα breaker that blocks RAS-mediated activation of AKT; or cetuximab, an anti-EGFR monoclonal antibody, BBO-11818 shows significantly enhanced efficacy in models harboring KRASG12D or KRASG12V mutations. BBO-11818 also shows a combination benefit with anti-PD-1 treatment, resulting in complete tumor regressions in the CT-26 syngeneic tumor mouse model. BBO-11818 is a potent pan-KRAS inhibitor with activity against both GTP and GDP forms of KRAS, presenting the opportunity to address, as monotherapy or combination, a large fraction of KRAS mutant tumors currently lacking targeted therapeutic options. Citation Format: Carlos Ernesto Stahlhut Espinosa, Kanchan Singh, Zuhui Zhang, Kyle Sullivan, Nadege Gitego, Megan Rigby, Roger Ma, Patrick Alexander, Saman Setoodeh, Jin Shu, Ken Lin, Dana Rabara, Erik Larsen, Alok Sharma, Albert Chan, Brian P. Smith, Andrew Stephen, Yue Yang, Jun Pei, Felice C. Lightstone, Dhirendra Simanshu, Rui Xu, Chunmei Ji, Keshi Wang, Bin Wang, Kerstin Sinkevicius, Dwight V. Nissley, Eli Wallace, Frank McCormick, Anna E. Maciag, Pedro J. Beltran. BBO-11818, an orally bioavailable, highly potent and non-covalent pan-KRAS inhibitor demonstrates robust anti-tumor activity in KRAS-mutant preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4378.