Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation

Yi Hsuan Chen, Hua Yi Hsu, Ming Tyng Yeh, Chen Cheng Chen, Chang Yu Huang, Ying Hsuan Chung, Zee Fen Chang, Wei Chen Kuo, Nei Li Chan, Jui Hsia Weng, Bon Chu Chung, Yu Ju Chen, Cheng Bang Jian, Ching Chieh Shen, Hwan Ching Tai, Sheh Yi Sheu, Jim Min Fang

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Targeting thymidylate kinase (TMPK) that catalyzes the phosphotransfer reaction for formation of dTDP from dTMP is a new strategy for anticancer treatment. This study is to understand the inhibitory mechanism of a previously identified human TMPK (hTMPK) inhibitor YMU1 (1a) by molecular docking, isothermal titration calorimetry, and photoaffinity labeling. The molecular dynamics simulation suggests that 1a prefers binding at the catalytic site of hTMPK, whereas the hTMPK inhibitors that bear pyridino[d]isothiazolone or benzo[d]isothiazolone core structure in lieu of the dimethylpyridine-fused isothiazolone moiety in 1a can have access to both the ATP-binding and catalytic sites. The binding sites of hTMPK inhibitors were validated by photoaffinity labeling and mass spectrometric studies. Taking together, 1a and its analogues stabilize the conformation of ligand-induced degradation (LID) region of hTMPK and block the catalytic site or ATP-binding site, thus attenuating the ATP binding-induced closed conformation that is required for phosphorylation of dTMP.

Original languageEnglish
Pages (from-to)9906-9918
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number21
DOIs
Publication statusPublished - Nov 10 2016

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation'. Together they form a unique fingerprint.

Cite this