Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme

  • Cell Chem Biol. 2019 Feb 21;26(2):278-288.e6. doi: 10.1016/j.chembiol.2018.10.026.
Yi-Jia Li  1 ,  Li Du  1 ,  Jianghai Wang  1 ,  Ramir Vega  1 ,  Terry D Lee  2 ,  Yunan Miao  2 ,  Grace Aldana-Masangkay  1 ,  Eric R Samuels  1 ,  Baozong Li  1 ,  S Xiaohu Ouyang  3 ,  Sharon A Colayco  4 ,  Ekaterina V Bobkova  4 ,  Daniela B Divlianska  4 ,  Eduard Sergienko  4 ,  Thomas D Y Chung  4 ,  Marwan Fakih  5 ,  Yuan Chen  6
Affiliations
  • 1. Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • 2. Department of Immunology, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA; Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, USA.
  • 3. SUMO Biosciences, Inc., 2265 E Foothill Boulevard, Pasadena, CA 91107, USA.
  • 4. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 5. Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
  • 6. Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA; Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, USA. Electronic address: [email protected].
PMID: 30581133 DOI: 10.1016/j.chembiol.2018.10.026
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.

Keywords
E1; KRas; SUMO; activating enzyme; allosteric inhibitor; c-Myc; cancer; covalent inhibitor; therapeutics; ubiquitin-like modification.
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