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

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, etc.

J Med Chem. 2016 Nov 10;59(21):9906-9918.

PMID: 27748121

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP902589962	YMU1		902589-96-2	Price

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