A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase
Jingjing Ruan, Dongdong Liang, Wenjing Yan, Yongwang Zhong, Daniel C. Talley, Ganesha Rai, Dingyin Tao, Christopher A. LeClair, Anton Simeonov, Ying‐Hua Zhang, Feihu Chen, Nancy L. Quinney, Susan E. Boyles, Deborah M. Cholon, Martina Gentzsch, Mark J. Henderson, Fengtian Xue, Shengyun Fang
Abstract
]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, which 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 promoting 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.