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(+) T cell responses, suggesting its therapeutic potential.
authors: Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Ravi K
authors: RK
authors: Anchoori
authors: Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Balasubramanyam
authors: B
authors: Karanam
authors: Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Shiwen
authors: S
authors: Peng
authors: Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Joshua W
authors: JW
authors: Wang
authors: Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Rosie
authors: R
authors: Jiang
authors: Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Toshihiko
authors: T
authors: Tanno
authors: Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Robert Z
authors: RZ
authors: Orlowski
authors: Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: William
authors: W
authors: Matsui
authors: Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Ming
authors: M
authors: Zhao
authors: Department of Oncology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Michelle A
authors: MA
authors: Rudek
authors: Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Chien-fu
authors: CF
authors: Hung
authors: 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.
authors: Xiang
authors: X
authors: Chen
authors: 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.
authors: Kylie J
authors: KJ
authors: Walters
authors: 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: roden@jhmi.edu.
authors: Richard B S
authors: RB
authors: Roden
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D005260:Female; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010881:Piperidones / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D054875:Ubiquitination
chemical_list: C500781:ADRM1 protein, human; D001897:Boronic Acids; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D010881:Piperidones; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib