Ravi K Anchoori, Rosie Jiang, Shiwen Peng, Ruey-Shyang Soong, Aliyah Algethami, Michelle A Rudek, Nicole Anders, Chien-Fu Hung, Xiang Chen, Xiuxiu Lu, Olumide Kayode, Marzena Dyba, Kylie J Walters, Richard B S Roden
Substitution of the m , p -chloro groups of bis-benzylidinepiperidone RA190 for p -nitro, generating RA183, enhanced covalent drug binding to Cys88 of RPN13. Treatment of cancer cell lines with RA183 inhibited ubiquitin-mediated protein degradation, resulting in rapid accumulation of high-molecular-weight polyubiquitinated proteins, blockade of NFκB signaling, endoplasmic reticulum stress, an unfolded protein response, production of reactive oxygen species, and apoptotic cell death. High-grade ovarian cancer, triple-negative breast cancer, and multiple myeloma cell lines were particularly vulnerable to RA183...
September 30, 2018: ACS Omega