| Literature DB >> 30581133 |
Yi-Jia Li1, Li Du1, Jianghai Wang1, Ramir Vega1, Terry D Lee2, Yunan Miao2, Grace Aldana-Masangkay1, Eric R Samuels1, Baozong Li1, S Xiaohu Ouyang3, Sharon A Colayco4, Ekaterina V Bobkova4, Daniela B Divlianska4, Eduard Sergienko4, Thomas D Y Chung4, Marwan Fakih5, Yuan Chen6.
Abstract
Ubiquitin-like (Ubl) post-translational modifications are potential targets for therapeutics. However, the only known mechanism for inhibiting a Ubl-activating enzyme is through targeting its ATP-binding site. Here we identify an allosteric inhibitory site in the small ubiquitin-like modifier (SUMO)-activating enzyme (E1). This site was unexpected because both it and analogous sites are deeply buried in all previously solved structures of E1s of ubiquitin-like modifiers (Ubl). The inhibitor not only suppresses SUMO E1 activity, but also enhances its degradation in vivo, presumably due to a conformational change induced by the compound. In addition, the lead compound increased the expression of miR-34b and reduced c-Myc levels in lymphoma and colorectal cancer cell lines and a colorectal cancer xenograft mouse model. Identification of this first-in-class inhibitor of SUMO E1 is a major advance in modulating Ubl modifications for therapeutic aims.Entities:
Keywords: E1; KRas; SUMO; activating enzyme; allosteric inhibitor; c-Myc; cancer; covalent inhibitor; therapeutics; ubiquitin-like modification
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Year: 2018 PMID： 30581133 PMCID： PMC6524651 DOI： 10.1016/j.chembiol.2018.10.026
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 8.116