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  3. A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase

A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase

  • Mol Biol Cell. 2022 Sep 8;mbcE22060233. doi: 10.1091/mbc.E22-06-0233.
Jingjing Ruan 1 2,  Dongdong Liang 3,  Wenjing Yan 1,  Yongwang Zhong 1,  Daniel C Talley 4,  Ganesha Rai 4,  Dingyin Tao 4,  Christopher A LeClair 4,  Anton Simeonov 4,  Yinghua Zhang 5,  Feihu Chen 6,  Nancy L Quinney 7,  Susan E Boyles 7,  Deborah M Cholon 7,  Martina Gentzsch 7 8 9,  Mark J Henderson 4,  Fengtian Xue 3,  Shengyun Fang 1
Affiliations

Affiliations

  • 1 Center for Biomedical Engineering and Technology, Department of Physiology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • 2 Anhui Medical University First Affiliated Hospital, Hefei, Anhui 230032, China.
  • 3 University of Maryland School of Pharmacy, Baltimore, USA.
  • 4 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
  • 5 Center for Innovative Biomedical Resources, Biosensor Core, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • 6 Anhui Medical University School of Parmacy, Hefei, Anhui 230032, China.
  • 7 Marsico Lung Institute and Cystic Fibrosis Research Center, The University of North Carolina, Chapel Hill, NC 27599, USA.
  • 8 University of North Carolina at Chapel Hill, Department of Pediatric Pulmonology, Chapel Hill, NC 27599, USA.
  • 9 University of North Carolina at Chapel Hill, Department of Cell Biology and Physiology, Chapel Hill, NC 27599, USA.
PMID: 36074076 DOI: 10.1091/mbc.E22-06-0233
Abstract

RNF5 E3 ubiquitin Ligase has multiple biological roles and has been linked to the development of severe diseases such as cystic fibrosis, acute myeloid leukemia, and certain viral infections, emphasizing the importance of discovering small molecule RNF5 modulators for research and drug development. The present study describes the synthesis of a new benzo[b]thiophene derivative, FX12 that acts as a selective small-molecule inhibitor and degrader of RNF5. We initially identified the previously reported STAT3 Inhibitor, Stattic, as an inhibitor of dislocation of misfolded proteins from the endoplasmic reticulum (ER) lumen to the cytosol in ER-associated degradation. A concise structure-activity relationship campaign (SAR) around the Stattic chemotype led to the synthesis of FX12 that has diminished activity in inhibition of STAT3 activation and retains dislocation inhibitory activity. FX12 binds to RNF5 and inhibits its E3 activity in vitro as well as promotes proteasomal degradation of RNF5 in cells. RNF5 as a molecular target for FX12 was supported by the facts that FX12 requires RNF5 to inhibit dislocation and negatively regulates RNF5 function. Thus, this study developed a small molecule inhibitor and degrader of the RNF5 ubiquitin Ligase, providing a chemical biology tool for RNF5 research and therapeutic development.

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