A bis-Benzylidine Piperidone Targeting Proteasome Ubiquitin Receptor RPN13/ADRM1 as a Therapy for Cancer

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 sensiti...

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Bibliographic Details
Published in:Cancer cell 2013-12, Vol.24 (6), p.791-805
Main Authors: Anchoori, Ravi K., Karanam, Balasubramanyam, Peng, Shiwen, Wang, Joshua W., Jiang, Rosie, Tanno, Toshihiko, Orlowski, Robert Z., Matsui, William, Zhao, Ming, Rudek, Michelle A., Hung, Chien-fu, Chen, Xiang, Walters, Kylie J., Roden, Richard B.S.
Format: Article
Language:English
Subjects:
Animals
Boronic Acids - pharmacology
Bortezomib
Cell Line, Tumor
Endoplasmic Reticulum Stress
Female
Genes, p53
Humans
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - chemistry
Membrane Glycoproteins - physiology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasms - drug therapy
Neoplasms - pathology
Piperidones - pharmacology
Proteasome Inhibitors - pharmacokinetics
Proteasome Inhibitors - pharmacology
Pyrazines - pharmacology
Ubiquitination
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Summary: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+ T cell responses, suggesting its therapeutic potential. [Display omitted] •The bis-benzylidine piperidone RA190 is an orally available proteasome inhibitor•RA190 covalently binds to cysteine 88 of human proteasomal ubiquitin receptor RPN13•Multiple myeloma, cervical, and ovarian cancers are particularly sensitive to RA190
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2013.11.001