Design, synthesis, and biological evaluation of benzodiazepine-based SUMO-specific protease 1 inhibitors

Zhitao Qiao; Weiwei Wang; Lie Wang; Donghua Wen; Yaxue Zhao; Qing Wang; Qingqing Meng; Guoqiang Chen; Yingli Wu; Huchen Zhou

doi:10.1016/j.bmcl.2011.08.101

Design, synthesis, and biological evaluation of benzodiazepine-based SUMO-specific protease 1 inhibitors

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6389-92. doi: 10.1016/j.bmcl.2011.08.101. Epub 2011 Sep 1.

Authors

Zhitao Qiao¹, Weiwei Wang, Lie Wang, Donghua Wen, Yaxue Zhao, Qing Wang, Qingqing Meng, Guoqiang Chen, Yingli Wu, Huchen Zhou

Affiliation

¹ School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.

PMID: 21930380
DOI: 10.1016/j.bmcl.2011.08.101

Abstract

As the best-characterized ubiquitin-like protein (UBL), small ubiquitin-related modifier (SUMO) was found to conjugate with a number of proteins to regulate cellular functions including transcription, signal transduction, and cell cycle. While E1, E2 and E3 ligases are responsible for the forward SUMOylation reaction, SUMO-specific proteases (SENPs) reversibly remove SUMO from the SUMOylated proteins. Recently, SENP1 was found to be a potential therapeutic target for the treatment of prostate cancers, but the design and synthesis of its inhibitors have not been reported. We designed and synthesized a series of benzodiazepine-based SENP1 inhibitors, and they showed inhibitory activity as good as IC(50)=9.2μM (compound 38). The structure-activity relationship was also discussed.

Publication types

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

MeSH terms

Cell Line, Tumor
Drug Design*
Drug Evaluation, Preclinical
Electrophoresis, Polyacrylamide Gel
Humans
Hydrogen Bonding
Inhibitory Concentration 50
Models, Molecular
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Small Ubiquitin-Related Modifier Proteins / metabolism*

Substances

Protease Inhibitors
Small Ubiquitin-Related Modifier Proteins