Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer

Ravi Anchoori, Rosie Jiang, Shiwen Peng, Ruey Shyang Soong, Aliyah Algethami, Michelle Rudek-Renaut, Nicole Anders, Chien-Fu Hung, Xiang Chen, Xiuxiu Lu, Olumide Kayode, Marzena Dyba, Kylie J. Walters, Richard S Roden

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11917-11929
Number of pages13
JournalACS Omega
Volume3
Issue number9
DOIs
StatePublished - Sep 30 2018

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Proteins
Cells
Tumors
Bearings (structural)
Firefly Luciferases
Degradation
Cell death
Proteasome Endopeptidase Complex
Ubiquitin
Liver
Reactive Oxygen Species
Substitution reactions
Molecular weight
Plasmas
Oxygen
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer. / Anchoori, Ravi; Jiang, Rosie; Peng, Shiwen; Soong, Ruey Shyang; Algethami, Aliyah; Rudek-Renaut, Michelle; Anders, Nicole; Hung, Chien-Fu; Chen, Xiang; Lu, Xiuxiu; Kayode, Olumide; Dyba, Marzena; Walters, Kylie J.; Roden, Richard S.

In: ACS Omega, Vol. 3, No. 9, 30.09.2018, p. 11917-11929.

Research output: Contribution to journalArticle

Anchoori, R, Jiang, R, Peng, S, Soong, RS, Algethami, A, Rudek-Renaut, M, Anders, N, Hung, C-F, Chen, X, Lu, X, Kayode, O, Dyba, M, Walters, KJ & Roden, RS 2018, 'Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer', ACS Omega, vol. 3, no. 9, pp. 11917-11929. https://doi.org/10.1021/acsomega.8b01479
Anchoori, Ravi ; Jiang, Rosie ; Peng, Shiwen ; Soong, Ruey Shyang ; Algethami, Aliyah ; Rudek-Renaut, Michelle ; Anders, Nicole ; Hung, Chien-Fu ; Chen, Xiang ; Lu, Xiuxiu ; Kayode, Olumide ; Dyba, Marzena ; Walters, Kylie J. ; Roden, Richard S. / Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer. In: ACS Omega. 2018 ; Vol. 3, No. 9. pp. 11917-11929.
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