A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer

Ravi K Anchoori; Balasubramanyam Karanam; Shiwen Peng; Joshua W Wang; Rosie Jiang; Toshihiko Tanno; Robert Z Orlowski; William Matsui; Ming Zhao; Michelle A Rudek; Chien-fu Hung; Xiang Chen; Kylie J Walters; Richard B S Roden

doi:10.1016/j.ccr.2013.11.001

A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer

Cancer Cell. 2013 Dec 9;24(6):791-805. doi: 10.1016/j.ccr.2013.11.001.

Affiliations

¹ Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
² Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
³ Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
⁵ Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA; Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA; Department of Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: [email protected].

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(+) T cell responses, suggesting its therapeutic potential.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Boronic Acids / pharmacology
Bortezomib
Cell Line, Tumor
Endoplasmic Reticulum Stress
Female
Genes, p53
Humans
Intracellular Signaling Peptides and Proteins
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

Substances

ADRM1 protein, human
Boronic Acids
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins
Piperidones
Proteasome Inhibitors
Pyrazines
Bortezomib

A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding