Son of Sevenless (SOS) is a guanine nucleotide exchange factor that activates the important cell signaling switch KRAS. SOS acts as a pacemaker for KRAS, the beating heart of cancer, by catalyzing the "beating" from the KRAS(off) to the KRAS(on) conformation[1].
BI-3406 is an orally active, highly potent and selective between KRAS and Son of Sevenless 1 (SOS1) interaction inhibitor (IC50: 6 nM), with anticancer activity. BI-3406 does not block the interaction of KRAS with SOS2 but elicits activity on a broad panel of KRAS oncogenic variants, including all major G12 and G13 oncoproteins. In KRAS-dependent cancers, BI-3406 potently reduces the formation of GTP-loaded KRAS, and inhibits MAPK pathway signaling. Down-modulation of this signaling cascade by BI-3406 in KRAS G12 or G13 mutant cells effectively limits cell proliferation[2]. BI-3406 inhibits SOS1 catalyzed formation of GTPKRAS in KRAS-mutant cells (IC50 = 83-231 nM), inhibits downstream signaling (pERK IC50 = 17-57nM), and inhibits proliferation in anchorage-independent 3D growth assays (IC50 = 16-52 nM) in a range of KRASmutant cells[1]. BI-3406 is an orally bioavailable compound and single administration was sufficient to reduce RAS-GTP and pERK levels in A549 xenograft tumors over a period of 24 hours and 7 hours, respectively. At a dose of 50 mg/kg bid, relevant levels of unbound exposures are achieved for the first 12 hours, when compared to unbound IC50 levels in A549 cells. In MIA PaCa-2 tumor bearing mice, twice daily compound treatment with 50 mg/kg BI-3406 resulted in pathway modulation over a period of up to 10 hours[3].
搜索
