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Issue 7, 2016
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Structure-based design of potent human dihydroorotate dehydrogenase inhibitors as anticancer agents

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Abstract

It has been proven that inhibiting human dihydroorotate dehydrogenase (hDHODH) restricts the growth of rapidly proliferating cells, thus hDHODH can be developed as a promising target for the treatment of immunological disease and cancer. Here, a succession of substituted hydrazino-thiazole derivatives were designed, synthesized, and biologically evaluated through structure-based optimization, of which compound 22 was the most potent inhibitor of hDHODH with an IC50 value of 1.8 nM. Furthermore, 22 exhibited much better antiproliferative activity than brequinar, both in HCT-116 and BxPC-3 cancer cell lines. Flow cytometry analysis revealed that 22 induced S phase cell cycle arrest and promoted induction of apoptosis. All results established a proof that blocking the pyrimidine de novo synthesis pathway by inhibiting the rate-limiting enzyme hDHODH is an attractive therapy for cancer.

Graphical abstract: Structure-based design of potent human dihydroorotate dehydrogenase inhibitors as anticancer agents

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Supplementary files

Article information


Submitted
29 Mar 2016
Accepted
07 Jun 2016
First published
13 Jun 2016

Med. Chem. Commun., 2016,7, 1441-1448
Article type
Research Article

Structure-based design of potent human dihydroorotate dehydrogenase inhibitors as anticancer agents

W. Song, S. Li, Y. Tong, J. Wang, L. Quan, Z. Chen, Z. Zhao, Y. Xu, L. Zhu, X. Qian and H. Li, Med. Chem. Commun., 2016, 7, 1441
DOI: 10.1039/C6MD00179C

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