Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy.

Author: Yanan LI ¹ ; Chaorong WANG ² ; Tiantian XU ¹ ; Peichen PAN ² ; Qing YU ¹ ; Lei XU ³ ; Xiufang XIONG ¹ ; Tingjun HOU ² ; Sunliang CUI ² ; Yi SUN ¹
Author Information

1. Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
3. Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 212013, China.
Publication Type:Journal Article
Keywords: Autophagy; Cullin RING ligase; ER stress; Neddylation; Small molecule inhibitor; mTORC1
From: Acta Pharmaceutica Sinica B 2021;11(11):3567-3584
CountryChina
Language:English
Abstract: Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both