Anticancer drug discovery by targeting cullin neddylation

作     者：Qing Yu Yihan Jiang Yi Sun Qing Yu;Yihan Jiang;Yi Sun

作者机构：Cancer Institute of the 2nd Affiliated HospitalInstitute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Division of Radiation and Cancer BiologyDepartment of Radiation OncologyUniversity of MichiganAnn ArborMI 48109.USA 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2020年第10卷第5期

页      面：746-765页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 100602[医学-中西医结合临床] 

基　　金：the financial support by the National Key R&D Program of China(2016YFA0501800 to YS) 

主　　题：Neddylation Anticancer Drug discovery Ubiquitin-proteasome system Small molecule inhibitors Virtual screen High-throughput screening 

摘      要：Protein neddylation is a post-translational modification which transfers the ubiquitin-like protein NEDD8 to a lysine residue of the target substrate through a three-step enzymatic cascade.The bestknown substrates of neddylation are cullin family proteins,which are the core component of Cullin-RING E3 ubiquitin ligases(CRLs).Given that cullin neddylation is required for CRL activity,and CRLs control the turn-over of a variety of key signal proteins and are often abnormally activated in cancers,targeting neddylation becomes a promising approach for discovery of novel anti-cancer therapeutics.In the past decade,we have witnessed significant progress in the field of protein neddylation from preclinical target validation,to drug screening,then to the clinical trials of neddylation inhibitors.In this review,we first briefly introduced the nature of protein neddylation and the regulation of neddylation cascade,followed by a summary of all reported chemical inhibitors of neddylation enzymes.We then discussed the structure-based targeting of protein-protein interaction in neddylation cascade,and finally the available approaches for the discovery of new neddylation inhibitors.This review will provide a focused,up-to-date and yet comprehensive overview on the discovery effort of neddylation inhibitors.