Fudotinib (JYP0322) is a potent, selective, next-generation, brain-penetrant macrocyclic ROS1 inhibitor with IC50 of 0.37 nM and 0.3 nM for ROS1 wild-type (WT) and ROS1G2032R, overcoming ROS1G2032R resistance.
JYP0322 demonstrates >130-fold selectivity over TRKA, shows moderate inhibition of TRKC (6-fold selectivity relative to ROS1) and weak activity against TRKB.
JYP0322 shows reduced potency against Ba/F3 LMNA-NTRK1 cells (IC50 = 37 nM) compared to repotrectinib (IC50 = 1.1 nM).
JYP0322 potently inhibits the proliferation of engineered cells with stable expression of CD74-ROS1 wild-type (WT) or clinically relevant mutants, including G2032R, S1986F/Y, G2033N, and G2101A.
JYP0322 demonstrated dose-dependent tumor growth inhibition (TGI) att doses of 1.5, 5, and 15 mg/kg administered twice daily (BID), achieved TGI rates of 83.5%, 101.4%, and 103.4%, respectively in Ba/F3 CD74-ROS1WT xenograft model.