BBO-8520 is a potent, selective and covalent inhibitor of KRAS G12C (ON), locks GTP-bound KRASG12C in the state 1 conformation resulting in rapid and complete blockade of effector binding.
BBO-8520 binds in the switch II pocket and covalently modifies both the (ON) and (OFF) forms of KRASG12C independently of any other partner proteins.
BBO-8520 inhibits KRASG12C (ON) by locking the GTP-bound protein in state 1.
BBO-8520 displays highly significant binding to KRAS G12C in a global cysteine proteome analysis and is 100x more selective for KRASG12C than for WT KRAS and other mutant isoforms, with no measurable activity against N- or H-RAS.
BBO-8520 has sub-nanomolar potency against KRASG12C mutant cell lines.
BBO-8520 rapidly and completely blocks the RAS-RAF1 interaction in effector binding assays, at least 30x more potent than sotorasib and adagrasib at preventing outgrowt in long-term clonogenic assays.
BBO-8520 (10 mg/kg, daily dosing, oral) causes significant tumor volume regression in the KrasG12C-p53 driven GEMM model, exhibits in vivo target engagement and pERK inhibition in the MIAPaCa-2 and H358 KRASG12C mutant tumor models.