BBO-11818

BBO-11818 is an orally active, highly selective (relative to NRAS and HRAS ), non-covalent pan- KRAS inhibitor ( IC₅₀ =28-120 nM). BBO-11818 specifically binds to the Switch-II/Helix 3 pocket, disrupts the KRAS:RAF1 interaction by inducing conformational changes, and blocks the MAPK signaling pathway. BBO-11818 exhibits significant anti-tumor activity, which not only inhibits cell proliferation and induces apoptosis, but also drives tumor regression in xenograft models. BBO-11818 produces synergistic effects when combined with Cetuximab, anti- PD-1 antibody or PI3Kα inhibitor. BBO-11818 is used in the research of KRAS mutation-related malignancies such as pancreatic cancer, non-small cell lung cancer and colorectal cancer ^{[1] [2]}.

In Vivo, BBO-11818 (10-100 mg/kg; p.o.; BID; 28 d) induces potent and statistically significant tumor growth inhibition and tumor regression in KRASG12D-mutant HPAC pancreatic cancer CDX models^[1]. BBO-11818 (10-100 mg/kg; p.o.; BID; 28 d) induces potent, dose-dependent, and statistically significant tumor growth inhibition in the KRASG12V-mutant H441 non-small cell lung cancer CDX model^[1]. BBO-11818 (100 mg/kg; p.o.; BID) induces a statistically significant reduction in tumor cell proliferation and promotes an increase in apoptosis levels in the KRASG12V-mutant Capan-2 pancreatic cancer CDX model^[1]. BBO-11818 (10-100 mg/kg; p.o.; single administration) exerts dose- and time-dependent inhibition of pERK and DUSP6 in KRASG12D pancreatic ductal adenocarcinoma (PDAC) xenografts, with an in vivo EC50 of 138 nmol/L for pERK inhibition; pERK levels are reduced by up to 85% following a single oral dose of 100 mg/kg^[2].

In Vitro, BBO-11818 (2.5 nM; 21 d) inhibits the long-term clonogenic growth of Capan-2 PDAC (KRASG12V) cells^[1]. BBO-11818 (3 nM; 15 d) inhibits the long-term clonogenic growth of LS513 colorectal cancer (KRASG12D) cells^[1]. BBO-11818 (30 nM; 4 h) potently and selectively inhibits SOS-mediated nucleotide exchange of KRAS (wild-type and oncogenic mutants), including the constitutively GTP-bound KRASA59G mutant, but shows no activity against NRAS^[2]. BBO-11818 (0.1-200 nM; 96 h) potently inhibits the viability of Ba/F3 cells driven by wild-type or oncogenic KRAS mutants, including the constitutively GTP-bound KRASA59G, while its activity is reduced in KRASG12R and KRASQ61X mutants^[2]. BBO-11818 (0-0.1 μM; 72 h & 96 h) potently and selectively inhibits 3D spheroid growth of human cancer cell lines driven by oncogenic KRAS mutations or KRAS amplification, while exhibiting extremely low activity in non-KRAS-driven cell lines^[2].

References:
[1]. Stahlhut C, Maciag A E, Sullivan K A, et al. Discovery of BBO-11818, a Potent and Selective Noncovalent Inhibitor of (ON) and (OFF) KRAS with Activity against Multiple Oncogenic Mutants[J]. Cancer Discovery, 2026: OF1-OF20.
[2]. Stahlhut C, et al. Discovery of BBO-11818, a Potent and Selective Noncovalent Inhibitor of (ON) and (OFF) KRAS with Activity against Multiple Oncogenic Mutants. Cancer Discov. Published online March 6, 2026.