De Novo Discovery of Thiopeptide Pseudo-natural Products Acting as Potent and Selective TNIK Kinase Inhibitors
Alexander A. Vinogradov, Yue Zhang, Keisuke Hamada, Jun Shi Chang, Chikako Okada, Hirotaka Nishimura, Naohiro Terasaka, Yuki Goto, Kazuhiro Ogata, Toru Sengoku, Hiroyasu Onaka, Hiroaki Suga
Abstract
= 3 nM). X-ray structural analysis of the TNIK/thiopeptide interaction revealed the unique mode of substrate-competitive inhibition exhibited by two of the discovered compounds. The thiopeptides internalized to the cytosol of HEK293H cells as efficiently as the known cell-penetrating peptide Tat (4-6 μM). Accordingly, the most potent compound, TP15, inhibited TNIK in HCT116 cells. Altogether, our platform enables the exploration of pseudo-natural thiopeptides with favorable pharmacological properties in drug discovery applications.
Topics & Concepts
Drug discoveryNatural productChemistryComputational biologyBiosynthesisKinaseEnzymeBiochemistryCytosolBiologyMicrobial Natural Products and BiosynthesisPeptidase Inhibition and AnalysisChemical Synthesis and Analysis