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

• DOI: 10.1091/mbc.e22-06-0233
• Publication Date: 2022-09-08T14:24:35Z
• Authors: Jingjing Ruan; Dongdong Liang; Wenjing Yan; Yongwang Zhong; Daniel C. Talley; Ganesha Rai; Dingyin Tao; Christopher A. Le...; Anton Simeonov; Yinghua Zhang; Feihu Chen; Nancy L. Quinney; Susan E. Boyles; Deborah M. Cholon; Martina Gentzsch; Mark J. Henderson; Fengtian Xue; Shengyun Fang
• Keywords: DNA-Binding Proteins; 0301 basic medicine; 03 medical and health sciences; Ubiquitin; Ubiquitin-Protein Ligases; Articles; Thiophenes; Cyclic S-Oxides; 3. Good health

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