Discovery of FLT3-targeting PROTACs with potent antiproliferative activity against acute myeloid leukemia cells harboring FLT3 mutations

Acute myeloid leukemia (AML) patients harboring Fms-like tyrosine kinase 3 (FLT3) mutations often suffer from poor prognosis and relapse. Targeted protein degradation utilizing proteolysis targeting chimeras (PROTACs) is considered as a novel therapeutic strategy in drug discovery and may be a promising modality to target FLT3 mutations for the development of potent anti-AML drugs. Herein, a kind of FLT3-targeting PROTACs was rationally developed based on a FLT3 Inhibitor previously reported by us. The representative compound 35 showed potent and selective antiproliferative activities against AML cells harboring FLT3 mutations. Western blot assay demonstrated that compound 35 effectively induced the degradation of FLT3-ITD and decreased the phosphorylation levels of FLT3-ITD, Akt, STAT5 and ERK in MV4-11 cells in a dose-dependent manner. Flow cytometry analysis illustrated that compound 35 strongly induced Apoptosis and cell cycle arrest in MV4-11 cells in a dose-dependent manner. Moreover, compound 35 displayed favorable metabolic stability in in-vitro liver microsomes studies. Comparative molecular dynamic (MD) simulation studies further elucidated the underlying mechanism of compound 35 to stabilize the dynamic ensemble of the FLT3-compound 35-cereblon (CRBN) ternary complex. Taken together, compound 35 could serve as a lead molecule for developing FLT3 degraders against AML.

AML; FLT3 mutation; MD simulation; PROTAC.