TIP-20

TIP-20 is a novel, small-molecule inhibitor of the Fms-like tyrosine kinase 3 (FLT3) receptor, specifically designed to target acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations. Identified through high-throughput virtual screening of the National Cancer Institute Developmental Therapeutics Program (NCI DTP) library, TIP-20 binds to the autoinhibited conformation of the FLT3 protein. It occupies the ATP-binding pocket and penetrates the DFG-out hydrophobic pocket, forming key hydrogen bonds with residues such as Glu-661 and Cys-694. In preclinical studies, TIP-20 has demonstrated potent antileukemic activity by inhibiting FLT3 kinase activity and suppressing downstream signaling pathways, including AKT, STAT5, and ERK. This inhibition leads to G0/G1 cell cycle arrest and induces apoptosis in FLT3-ITD positive AML cell lines, such as MV4-11 and MOLM-13, while showing significantly lower sensitivity in wild-type cells.