BBO-11818 is a potent, selective, orally bioavailable noncovalent pan-KRAS inhibitor, potently disrupts the interaction of RAF1-RAS Binding Domain (RBD) with KRASG12D (IC50=28 nM), KRASG12V (IC50=61 nM), KRASG12C (IC50=47 nM), and KRASG12R (IC50=51 nM), as well as KRASWT (IC50=120 nM).
BBO-11818 inhibits multiple KRAS mutants in both the inactive GDP-bound (OFF) and active GTP-bound (ON) states.
BBO-11818 potently inhibits SOS-mediated nucleotide exchange of KRAS WT and oncogenic mutants but not NRAS WT.
BBO-11818 is highly potent in multiple KRAS-mutant cells, including those with KRASG12D, KRASG12V, and KRASG12C, with pERK inhibition EC50 values ranging from 0.356 to 28.1 nM, also potently inhibits pERKin a cell line harboring KRASAMP with EC50 of 4.35 nM.
BBO-11818 does not inhibit pERK in cell lines not driven by KRAS.
BBO-11818 also showed limited potency in the KRASG12R and KRASQ61X lines tested (EC50 = 357 and 278 nmol/L, respectively.
BBO-11818 inhibits cellular viability in cells harboring the clinically important mutants KRASG12D, KRASG12V, and KRASG12C, with mean EC50 values of 2.21, 31.2, and 2.26 nmol/L, respectively.
BBO-11818 produced tumor regressions in KRAS-mutant xenograft models, strongly reduced tumor pERK and DUSP6 levels in a dose- and time-dependent manner.