Synthesis and biological evaluation of thiazole derivatives as novel USP7 inhibitors

Chao Chen; Jiemei Song; Jinzheng Wang; Chang Xu; Caiping Chen; Wei Gu; Hongbin Sun; Xiaoan Wen

doi:10.1016/j.bmcl.2017.01.018

Synthesis and biological evaluation of thiazole derivatives as novel USP7 inhibitors

Bioorg Med Chem Lett. 2017 Feb 15;27(4):845-849. doi: 10.1016/j.bmcl.2017.01.018. Epub 2017 Jan 10.

Authors

Chao Chen¹, Jiemei Song¹, Jinzheng Wang¹, Chang Xu¹, Caiping Chen¹, Wei Gu², Hongbin Sun³, Xiaoan Wen⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
² Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
³ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: hongbinsun@cpu.edu.cn.
⁴ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: wxagj@126.com.

PMID: 28108249
DOI: 10.1016/j.bmcl.2017.01.018

Abstract

Herpesvirus-associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with and stabilizes Mdm2, and represents one of the first examples that deubiquitinases oncogenic proteins. USP7 has been regarded as a potential drug target for cancer therapy. Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo. Based on leading USP7 inhibitors P5091 and P22077, we designed and synthesized a series of thiazole derivatives. The results of in vitro assays showed that the thiazole compounds exhibited low micromolar inhibition activity against both USP7 enzyme and cancer cell lines. The compounds induced cell death in a p53-dependent and p53-independent manner. Taken together, this study may provide thiazole compounds as a new class of USP7 inhibitors.

Keywords: Human colon cancer; Thiazole derivatives; USP7 inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Binding Sites
Crystallography, X-Ray
Enzyme Activation / drug effects
HCT116 Cells
Humans
Inhibitory Concentration 50
Molecular Conformation
Molecular Docking Simulation
Protein Binding
Protein Structure, Tertiary
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacology*
Tumor Suppressor Protein p53 / metabolism
Ubiquitin Thiolesterase / antagonists & inhibitors*
Ubiquitin Thiolesterase / metabolism
Ubiquitin-Specific Peptidase 7

Substances

Antineoplastic Agents
Thiazoles
Tumor Suppressor Protein p53
USP7 protein, human
Ubiquitin Thiolesterase
Ubiquitin-Specific Peptidase 7