SMU-037 is an orally bioavailable, selective ROS1 inhibitor with potent activity (IC₅₀= 6.8 nM) and the ability to penetrate the blood-brain barrier. It exhibits approximately 25-fold selectivity for ALK and demonstrates remarkable sensitivity to the G2032R resistance mutation. SMU-037 inhibits the phosphorylation of ROS1 and its downstream MAPK-ERK signaling pathway, leading to cell cycle arrest and apoptosis. It effectively suppresses tumor growth in both subcutaneous and intracranial xenograft mouse models. SMU-037 is applicable for research related to non-small cell lung cancer (NSCLC).

SMU-037 (compound 9y) exhibits significant activity against A549 (IC 50 = 0.9 μM), HCC-78 (IC 50 = 1.1 μM), and NCI-H3122 (IC 50 = 1.1 μM) cells, as well as noteworthy inhibition of Ba/F3 ROS1 G2032R and Ba/F3 ROS1 L2026R cells with IC 50 values of 8.9 nM and 32.0 nM, respectively. At concentrations of 0.001-3 μM for 8 hours, SMU-037 reduces ROS1 and its downstream MAPK-ERK phosphorylation in various Ba/F3 and A549 cells in a dose-dependent manner. Additionally, SMU-037 (0-100 nM, 48 hours) causes cell cycle arrest, halting ROS1 WT cells in the G0/G1 phase and ROS1 G2032R cells in the G2/M phase, and induces apoptosis in Ba/F3-ROS1 WT and Ba/F3-ROS1 G2032R cells.

SMU-037, administered orally at doses of 15, 30, and 60 mg/kg daily for 14 consecutive days, demonstrates significant tumor growth inhibition in xenograft and brain metastasis mouse models.