TY - JOUR
T1 - Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer
AU - Anchoori, Ravi K.
AU - Jiang, Rosie
AU - Peng, Shiwen
AU - Soong, Ruey Shyang
AU - Algethami, Aliyah
AU - Rudek, Michelle A.
AU - Anders, Nicole
AU - Hung, Chien Fu
AU - Chen, Xiang
AU - Lu, Xiuxiu
AU - Kayode, Olumide
AU - Dyba, Marzena
AU - Walters, Kylie J.
AU - Roden, Richard B.S.
N1 - Funding Information:
The authors thank D. Piwnica-Worms (Washington University, St. Louis, MO) for the 4UbFL plasmid. This work was supported by the Intramural Research Program of the NCI, National Institutes of Health Center for Cancer Research (to K.J.W.), and grant support was provided by National Institutes of Health grant P50 CA098252, the Alleghany Health Network-Johns Hopkins Cancer Research Fund, and the Ovarian Cancer Research Fund Alliance #458972 (to R.K.A., C.-F.H., and R.B.S.R.). 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) and the Dr. Richard W. TeLinde endowment. This project was funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/9/30
Y1 - 2018/9/30
N2 - Substitution of the m,p-chloro groups of bis-benzylidinepiperidone RA190 for p-nitro, generating RA183, enhanced covalent drug binding to Cys88 of RPN13. Treatment of cancer cell lines with RA183 inhibited ubiquitin-mediated protein degradation, resulting in rapid accumulation of high-molecular-weight polyubiquitinated proteins, blockade of NFκB signaling, endoplasmic reticulum stress, an unfolded protein response, production of reactive oxygen species, and apoptotic cell death. High-grade ovarian cancer, triple-negative breast cancer, and multiple myeloma cell lines were particularly vulnerable to RA183. RA183 stabilized a tetraubiquitin-linked firefly luciferase reporter protein in cancer cell lines and mice, demonstrating in vitro and in vivo proteasomal inhibition, respectively. However, RA183 was rapidly cleared from plasma, likely reflecting its rapid degradation to the active compound RA9, as seen in human liver microsomes. Intraperitoneal administration of RA183 inhibited proteasome function and orthotopic tumor growth in mice bearing human ovarian cancer model ES2-luc ascites or syngeneic ID8-luc tumor.
AB - Substitution of the m,p-chloro groups of bis-benzylidinepiperidone RA190 for p-nitro, generating RA183, enhanced covalent drug binding to Cys88 of RPN13. Treatment of cancer cell lines with RA183 inhibited ubiquitin-mediated protein degradation, resulting in rapid accumulation of high-molecular-weight polyubiquitinated proteins, blockade of NFκB signaling, endoplasmic reticulum stress, an unfolded protein response, production of reactive oxygen species, and apoptotic cell death. High-grade ovarian cancer, triple-negative breast cancer, and multiple myeloma cell lines were particularly vulnerable to RA183. RA183 stabilized a tetraubiquitin-linked firefly luciferase reporter protein in cancer cell lines and mice, demonstrating in vitro and in vivo proteasomal inhibition, respectively. However, RA183 was rapidly cleared from plasma, likely reflecting its rapid degradation to the active compound RA9, as seen in human liver microsomes. Intraperitoneal administration of RA183 inhibited proteasome function and orthotopic tumor growth in mice bearing human ovarian cancer model ES2-luc ascites or syngeneic ID8-luc tumor.
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U2 - 10.1021/acsomega.8b01479
DO - 10.1021/acsomega.8b01479
M3 - Article
AN - SCOPUS:85054329120
SN - 2470-1343
VL - 3
SP - 11917
EP - 11929
JO - ACS Omega
JF - ACS Omega
IS - 9
ER -