Discovery of a Potent and Selective FLT3 Inhibitor (Z)-N-(5-((5-Fluoro-2-oxoindolin-3-ylidene)methyl)-4-methyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propanamide with Improved Drug-like Properties and Superior Efficacy in FLT3-ITD-Positive Acute Myeloid Leukemia

Overcoming the FLT3-ITD mutant has been a promising drug design strategy for treating acute myeloid leukemia (AML). Herein, we discovered a novel FLT3 inhibitor 17, which displayed potent inhibitory activity against the FLT3-ITD mutant (IC50 = 0.8 nM) and achieved good selectivity over c-KIT kinase (over 500-fold). Compound 17 selectively inhibited the proliferation of FLT3-ITD-positive AML cell lines MV4-11 (IC50 = 23.5 nM) and MOLM-13 (IC50 = 35.5 nM) and exhibited potent inhibitory effects against associated acquired resistance mutations. In cellular mechanism studies, compound 17 strongly inhibited FLT3-mediated signaling pathways and induced apoptosis by arresting the cell cycle in the sub-G1 phase. In in vivo studies, compound 17 demonstrated a good bioavailability (73.6%) and significantly suppressed tumor growth in MV4-11 (10 mg/kg, TGI 93.4%) and MOLM-13 (20 mg/kg, TGI 98.0%) xenograft models without exhibiting obvious toxicity. These results suggested that compound 17 may be a promising drug candidate for treating FLT3-ITD-positive AML.

Automated summary

Compound 17, a novel FLT3 inhibitor, demonstrated potent inhibitory activity and good selectivity against FLT3-ITD-positive AML, as well as strong inhibitory effects against associated acquired resistance mutations. In vivo studies showed that compound 17 significantly suppressed tumor growth without obvious toxicity, suggesting its potential as a promising drug candidate for treating FLT3-ITD-positive AML.