Abstract 7104: 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 commonly mutated in human cancer. Inhibitors of KRASG12C have shown promising clinical efficacy; however, there are currently no approved targeted therapies against other KRAS variants, and a significant underserved patient population across several major cancer types, including pancreatic carcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC), remains. We discovered BBO-11818: a potent, selective, orally bioavailable small molecule KRAS inhibitor with activity against multiple KRAS mutants, including KRASG12D and KRASG12V, in both their active GTP-bound (ON) and inactive GDP-bound (OFF) states. BBO-11818 binds the switch II pocket with high affinity and selectivity, locking the active form in the signaling-incompetent state 1 to disrupt the association of GTP-bound KRAS with its key effector RAF1, and sequestering the inactive form. BBO-11818 potently inhibits several oncogenic KRAS mutants in cell-based assays, 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. 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 clinical-stage (NCT06625775), selective RAS:PI3Kα breaker that blocks RAS-mediated activation of the PI3Kα-AKT pathway, 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 shows combination benefit with anti-PD-1, 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 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 E. Stahlhut Espinosa, 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, Molly Grandcolas, 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 V. Nissley, Eli Wallace, Bin Wang, Kerstin 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 American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7104.