@article{3f94316d2faa44fa8f2d04a884169dab,
title = "A bis-Benzylidine Piperidone Targeting Proteasome Ubiquitin Receptor RPN13/ADRM1 as a Therapy for Cancer",
abstract = "The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, even those resistant to bortezomib, were sensitive to RA190 via endoplasmic reticulum stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After oral or intraperitoneal dosing of mice, RA190 distributed to plasma and major organs except the brain and inhibited proteasome function in skin and muscle. RA190 administration profoundly reduced growth of MM and ovarian cancer xenografts, and oral RA190 treatment retarded HPV16+ syngeneic mouse tumor growth, without affecting spontaneous HPV-specific CD8+ Tcell responses, suggesting its therapeutic potential.",
author = "Anchoori, {Ravi K.} and Balasubramanyam Karanam and Shiwen Peng and Wang, {Joshua W.} and Rosie Jiang and Toshihiko Tanno and Orlowski, {Robert Z.} and William Matsui and Ming Zhao and Rudek, {Michelle A.} and Hung, {Chien fu} and Xiang Chen and Walters, {Kylie J.} and Roden, {Richard B.S.}",
note = "Funding Information: We thank B. Vogelstein (Johns Hopkins University) for the HCT116 lines and D. Piwnica-Worms (Washington University, St. Louis, MO) for the 4UbFL and FL plasmids. Grant support was provided by National Institutes of Health ATIP Program grants P50 CA098252 and CA136472 and the M.D. Anderson Cancer Center Specialized Program of Research Excellence in Multiple Myeloma (P50 CA142509). The project was supported in part by the Sidney Kimmel Comprehensive Cancer Center Analytical Pharmacology Core at Johns Hopkins (P30 CA006973 and UL1 RR 025005). We also thank the HERA Foundation and the Ephraim and Wilma Shaw Roseman Foundation for support. NMR data were acquired in the NMR facility at the University of Minnesota, and data processing and depiction occurred in the Minnesota Supercomputing Institute Basic Sciences Computing Lab. We also thank P. Villalta (University of Minnesota) for his help with the LC-MS and E. Arriaga (University of Minnesota) for allowing us to use his spectrofluorometer. ",
year = "2013",
month = dec,
day = "9",
doi = "10.1016/j.ccr.2013.11.001",
language = "English (US)",
volume = "24",
pages = "791--805",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}