RA375

RA375 is a small molecule inhibitor of the ubiquitin receptor RPN13 (also known as ADRM1), which is a component of the 19S regulatory particle of the proteasome. Developed as a more potent successor to RA190, RA375 is a bis-benzylidine piperidone-based Michael acceptor that covalently adducts Cysteine 88 of RPN13. It features nitro ring substituents and an additional chloroacetamide warhead, which contribute to its ten-fold greater activity compared to its predecessor. By inhibiting RPN13, RA375 triggers a rapid accumulation of high molecular weight polyubiquitinated proteins, reduces intracellular glutathione levels, and induces endoplasmic reticulum and oxidative stress, ultimately leading to apoptosis. Preclinical studies have demonstrated its efficacy against multiple myeloma and various solid cancers, including ovarian, cervical, and head and neck cancers, with enhanced sensitivity observed in HPV-associated and ARID1A-deficient cell lines.