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 journalArticle

2 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

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dTMP kinase
Phosphates
Ligands
Catalytic Domain
Adenosine Triphosphate
Binding Sites
Calorimetry
Molecular Dynamics Simulation
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation. / Chen, Yi Hsuan; Hsu, Hua Yi; Yeh, Ming Tyng; Chen, Chen Cheng; Huang, Chang Yu; Chung, Ying Hsuan; Chang, Zee Fen; Kuo, Wei Chen; Chan, Nei Li; Weng, Jui Hsia; Chung, Bon Chu; Chen, Yu Ju; Jian, Cheng Bang; Shen, Ching Chieh; Tai, Hwan Ching; Sheu, Sheh Yi; Fang, Jim Min.

In: Journal of Medicinal Chemistry, Vol. 59, No. 21, 10.11.2016, p. 9906-9918.

Research output: Contribution to journalArticle

Chen, YH, Hsu, HY, Yeh, MT, Chen, CC, Huang, CY, Chung, YH, Chang, ZF, Kuo, WC, Chan, NL, Weng, JH, Chung, BC, Chen, YJ, Jian, CB, Shen, CC, Tai, HC, Sheu, SY & Fang, JM 2016, 'Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation', Journal of Medicinal Chemistry, vol. 59, no. 21, pp. 9906-9918. https://doi.org/10.1021/acs.jmedchem.6b01280
Chen, Yi Hsuan ; Hsu, Hua Yi ; Yeh, Ming Tyng ; Chen, Chen Cheng ; Huang, Chang Yu ; Chung, Ying Hsuan ; Chang, Zee Fen ; Kuo, Wei Chen ; Chan, Nei Li ; Weng, Jui Hsia ; Chung, Bon Chu ; Chen, Yu Ju ; Jian, Cheng Bang ; Shen, Ching Chieh ; Tai, Hwan Ching ; Sheu, Sheh Yi ; Fang, Jim Min. / Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 21. pp. 9906-9918.
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