Discovery of TRD‐93 as a novel DRAK2 inhibitor

Death-associated protein kinase-related apoptosis-inducing protein kinase 2 (DRAK2) has become a promising target for drug development. In search of novel and selective DRAK2 inhibitor motif, in vitro screen kinase assay was established performed using in-house chemical libraries. After through hit triage procedure, N-2-(3,5-dichlorophenyl)-5-fluoro-N-4-methylpyrimidine-2,4-diamine (1) was selected as initial hit with structural novelty and drug-likeness. During hit validation, structure-activity relationship of 1 was thoroughly disclosed and TRD-93 was finally validated as hit for DRAK2 inhibition. TRD-93 is small (mw = 290) but selectively potent to DRAK2 (IC50 = 0.16 mu M) over other kinases including DAPK family kinases. Molecular binding model study of TRD-93 to DRAK2 is also discussed.