Identification of 2,4-disubstitued pyridine derivatives as potent FMS-like tyrosine receptor kinase 3 (FLT3) inhibitors.

Accumulating evidence has shown that FMS-like tyrosine receptor kinase 3 (FLT3) activity plays a critical role in a substantial proportion of patients diagnosed with acute myeloid leukemia (AML), making it a potential molecular target for therapeutic intervention in AML treatment. Herein, a series of 2,4-disubstitued pyridine analogs, originating from the lead entity Liao-12y, were designed and synthesized. The most promising compound 6z, displayed single-digit nanomolar IC50 values against FLT3-ITD in both enzymatic and cellular assays, with selectivity over both FLT3 WT (32-fold) and c-KIT (180-fold) transformed BaF3 cells. Moreover, 6z suppressed the proliferation of FLT3-ITD driven MOLM-13 cells by blocking FLT3 phosphorylation and its downstream cascades (Akt, STAT5, and ERK), leading to cell cycle arrest and induction of apoptosis. In in vivo pharmacokinetic (PK) studies, 6z displayed suitable intravenous PK parameters but suboptimal oral PK parameters. Overall, compound 6z holds potential as a robust lead compound for further advancement of therapeutic remedies for AML.