BBO-8520 is a direct small molecule covalent inhibitor targeting KRAS G12C with high oral availability. BBO-8520 has the characteristics of KRAS G12C (OFF) inhibitor and the function of blocking KRAS G12C (ON) signal. BBO-8520 inhibits cell proliferation by inhibiting KRAS G12C (ON) by binding GTP protein. BBO-8520 can block RAS-RAF1 interaction and return KRAS G12C to the inactive (OFF) state .
BBO-8520 (10 mg/kg/d; po) causes inhibition of pERK and KRASG12C activation in a KrasG12C-p53-driven GEMM model, leading to durable tumor regression. BBO-8520 demonstrates strong dose-dependent and time-dependent pharmacodynamic effects (more than 80% inhibition of pERK) in mice with KRASG12C mutant tumors[1].
References:
[1]. Maciag A E, et al. Abstract ND07: BBO-8520, a first-in-class, direct inhibitor of KRASG12C (ON), locks GTP-bound KRASG12C in the state 1 conformation resulting in rapid and complete blockade of effector binding[J]. Cancer Research, 2024, 84(7_Supplement): ND07-ND07. [2]. Caughey B A, Strickler J H. Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies[J]. Drugs, 2024, 84(1): 27-44.