2. Academic Validation
  3. Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme

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

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: ychen@coh.org.
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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