RA-9

RA-9 (CAS No.: 919091-63-7) is a potent, cell-permeable small-molecule inhibitor of proteasome-associated deubiquitinating enzymes (DUBs), broadly used in cancer biology and protein homeostasis research. It targets multiple DUBs, including UCH-L1, UCH-L3, USP8, and USP5, and functionally impairs the 26S proteasome without affecting the core 20S proteolytic activity, thereby disrupting ubiquitin-dependent protein degradation and promoting the accumulation of polyubiquitinated proteins. Mechanistically, RA-9 induces pronounced endoplasmic reticulum stress and activation of the unfolded protein response, as evidenced by increased phosphorylation of eIF2α and upregulation of stress markers such as GRP78, ultimately leading to apoptotic cell death. In vitro, RA-9 exhibits cytotoxic activity across a range of cancer cell lines, including ovarian and cervical models, with efficacy typically observed in the low micromolar range and accompanied by cell cycle arrest at S and G2/M phases. It demonstrates selective antiproliferative effects in ovarian cancer cell lines and primary patient-derived cells, highlighting its relevance for translational oncology studies. In vivo, RA-9 has been shown to reduce tumor burden and ascites formation while prolonging survival in ovarian cancer xenograft models, with minimal apparent host toxicity. This compound is widely applied in studies of proteostasis, ER stress signaling, and ubiquitin–proteasome system modulation, and its experimental concentrations or dosing regimens are typically optimized according to specific cellular or animal model systems.