Abstract A063: BBO-11818: an orally bioavailable, highly potent and selective non-covalent pan-KRAS(ON) and (OFF) inhibitor with robust anti-tumor activity in KRAS-mutant preclinical models

Abstract KRAS is one of the most commonly mutated oncogenes, 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). Here, we report on BBO-11818: a potent, selective, orally bioavailable small molecule KRAS inhibitor with activity against multiple KRAS mutants, including KRASG12D and KRASG12V, in both their inactive GDP-bound (OFF) and active GTP-bound (ON) states. BBO-11818 binds a switch II pocket in mutant KRAS with high affinity and selectivity in its active and inactive conformations, sequestering the inactive form and locking the active form in the signaling-incompetent 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 oncogenic KRAS mutants, resulting in the suppression of MAPK signaling and inhibition of cell proliferation with single-digit 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 and patient-derived xenograft (PDX) models of KRAS-mutant PDAC, NSCLC, and CRC. Combination treatment with BBO-10203, a selective RAS:PI3Kα breaker that blocks RAS-mediated activation of the PI3K-AKT pathway (NCT06625775), results in decreased cellular proliferation, increased apoptosis, and enhanced efficacy in CDX and PDX models harboring KRASG12D or KRASG12V mutations. Similarly, combination treatment with BBO-11818 and cetuximab, an approved anti-EGFR monoclonal antibody, results in enhanced anti-tumor activity in a KRASG12D CDX model. Finally, BBO-11818 also shows a combination benefit with anti-PD-1 treatment, resulting in complete tumor regressions in the KRASG12D CT-26 syngeneic tumor mouse model. BBO-11818 is a potent pan-KRAS inhibitor with activity against both the GTP- and GDP-bound states of KRAS, presenting the opportunity to address, as monotherapy or combination, a large fraction of KRAS mutant tumors currently lacking targeted therapeutic options. BBO-11818 has entered Phase 1 clinical trials for patients with various KRAS mutations in colorectal, pancreatic, and lung cancers (NCT06917079). Citation Format: 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 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 Nissley, Eli Wallace, Bin Wang, Kerstin W. Sinkevicius, Frank McCormick, Pedro J. Beltran. BBO-11818: an orally bioavailable, highly potent and selective non-covalent pan-KRAS(ON) and (OFF) inhibitor with robust anti-tumor activity in KRAS-mutant preclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A063.