Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors

Zirui Lü; Xiaona Li; Kebin Li; Cong Wang; Tingting Du; Wei Huang; Ming Ji; Changhong Li; Fengrong Xu; Ping Xu; Yan Niu

doi:10.1021/acsmedchemlett.0c00544

Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors

ACS Med Chem Lett. 2021 Apr 1;12(5):696-703. doi: 10.1021/acsmedchemlett.0c00544. eCollection 2021 May 13.

Authors

Zirui Lü¹, Xiaona Li¹, Kebin Li¹, Cong Wang¹, Tingting Du², Wei Huang², Ming Ji², Changhong Li³, Fengrong Xu¹, Ping Xu¹, Yan Niu¹

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, P. R. China.
² Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100050, P. R. China.
³ Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, P. R. China.

Abstract

We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.