SAF-189s is a potent, highly selective, brain-penetrant, next-generation inhibitor of ALK and ROS1 with IC50 of 1 nM and 0.5 nM, respectively, inhibits ROS1 fusion wild-type and crizotinib-resistant mutants (ROS1 G2032R mutant, IC50=12.4 nM).
SAF-189s is more potent than crizotinib and ceritinib and comparable to lorlatinib.
SAF-189s effectively inhibits the kinase activity of a series of reported crizotinib-resistant ROS1 mutants, especially the most frequently identified mutant, ROS1G2032R.
SAF-189s is an ATP-competitive manner to inhibit ROS1 kinases, with notable potency against a series of crizotinib-resistant mutants, including ROS1G2032R.
SAF-189s displays more than 200-fold (214 kinases) or 20-fold (74 kinases) selectivity in a panel of 288 tested kinases.
SAF-189s (25-100 nM) suppresses ROS1 pathway activation in HCC78 cells.
SAF-189s potently inhibits cell proliferation driven by ROS1 fusion wt and resistance mutants, has IC50 values of 49.4 and 1.1 nM for HCC78 and BaF3/CD74–ROS1 cells, both of which harbor the wt ROS1 fusion, inhibits BaF3 cells expressing the G2032R and L2026M-mutated ROS1 fusion protein with IC50 of 141.0 and 3.1 nM respectively, also significantly inhibits the proliferation of BaF3 cells expressing other resistance mutants, including the S1986F, S1986Y, and D2033N mutants.
SAF-189s shows potent antitumor efficacy against ROS1 wt- and G2032R mutant-driven tumors.