BBO-11818

BBO-11818 is an orally active, non-covalent pan-KRAS inhibitor that simultaneously targets both the inactivated and activated forms of the KRAS protein, inhibiting a wide range of oncogenic mutants. BBO-11818 significantly inhibits the MAPK/ERK signaling pathway and the proliferation of KRAS-mutated tumor cells. It is currently being evaluated in the KONQUER-101 Phase I clinical trial for the treatment of KRAS-mutated solid tumors.

KRas (WT):28 nM, KRas (G12C):51 nM, KRas (G12R):120 nM, KRAS (G12D):61 nM, KRas (G12V):47 nM

BBO-11818 (2.5 nM; 21 days) inhibits long-term colony formation in Capan-2 PDAC (KRASG12V) cells [1].
BBO-11818 (3 nM; 15 days) inhibits long-term colony formation in LS513 colorectal cancer (KRASG12D) cells [1].
BBO-11818 (30 nM; 4 h) potently and selectively inhibits SOS-mediated nucleotide exchange in KRAS (wild-type and oncogenic mutants), including the constitutive GTP-binding 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 KRAS A59G mutant), while its activity is reduced in KRAS G12R and KRAS Q61X mutants [2].
BBO-11818 (0–0.1 μM; 72 h & 96 h) potently and selectively inhibits the growth of 3D spheroids in human cancer cell lines driven by oncogenic KRAS mutations or KRAS amplification, while exhibiting minimal activity in non-KRAS-driven cell lines [2].

BBO-11818 (10–100 mg/kg; oral; twice daily; 28 days) induces potent and statistically significant tumor growth inhibition and tumor regression in the HPAC pancreatic cancer CDX model harboring the KRASG12D mutation [1].
BBO-11818 (10–100 mg/kg; oral; twice daily; 28 days) induces dose-dependent, statistically significant tumor growth inhibition in the KRASG12V-mutant Capan-2 pancreatic cancer CDX model [1].
BBO-11818 (10–100 mg/kg; p.o.; BID; 28 d) induces potent and statistically significant tumor growth inhibition and tumor regression in the KRASG12D/PIK3CAH1047L-mutant GP2d colorectal cancer CDX model [1].
BBO-11818 (10–100 mg/kg; p.o.; BID; 28 days) 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 (10–100 mg/kg; p.o.; single dose) can suppress pERK activity in a dose-dependent manner (down to ~10% of the solvent control) and persistently (for up to 24 h) in a KRASG12D-mutant HPAC pancreatic cancer CDX model [1].
BBO-11818 (100 mg/kg; p.o.; BID) induces a statistically significant reduction in tumor cell proliferation and promotes increased levels of apoptosis in the KRASG12V-mutant Capan-2 pancreatic cancer CDX model [1].