Discovery of FYJ-195 as a Highly Potent FLT3 Inhibitor against Multiple Acquired Resistance Mutations in Acute Myeloid Leukemia

The efficacy of FLT3 inhibitors in acute myeloid leukemia (AML) is severely limited by resistance mutations, particularly the recalcitrant gatekeeper F691L and activation loop D835V/Y variants. Herein, through the structure-guided optimization of our previously reported lead SILA-123, we identified FYJ-195, a highly potent type II FLT3 inhibitor capable of overcoming these recalcitrant mutants. FYJ-195 exhibited single-digit nanomolar potency against Ba/F3-FLT3-ITD-F691L (IC50 = 9.09 nM) and subnanomolar activity against Ba/F3-FLT3-ITD-D835Y (IC50 = 4.64 nM) and Ba/F3-FLT3-ITD-D835V (IC50 = 0.76 nM). In vivo, FYJ-195 induced profound tumor regression (TGI = 125%) in the MV4-11 xenograft model (10 mg/kg) and achieved robust tumor growth suppression (TGI = 68.6%) in the Ba/F3-FLT3-ITD-F691L model (50 mg/kg), where quizartinib was ineffective. Mechanistic studies confirmed that FYJ-195 effectively blocked FLT3 signaling and induced apoptosis without observable toxicity. Collectively, FYJ-195 represents a promising lead candidate for drug-resistant AML.