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

作者：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^*

来源：Cancer Cell, 2013, 24(6): 791-805.

DOI：10.1016/j.ccr.2013.11.001

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 papillonnavirus (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.

• 出版日期2013-12-9