Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties

English version

Autoři: Ravi K. Anchoori ^aff001; Marietta Tan ^aff003; Ssu-Hsueh Tseng ^aff001; Shiwen Peng ^aff001; Ruey-Shyang Soong ^aff001; Aliyah Algethami ^aff001; Palmer Foran ^aff001; Samarjit Das ^aff001; Chenguang Wang ^aff005; Tian-Li Wang ^aff001; Hong Liang ^aff001; Chien-Fu Hung ^aff001; Richard B. S. Roden ^aff001
Působiště autorů: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America ^aff001; Department of Oncology, The Johns Hopkins University, Baltimore, Maryland, United States of America ^aff002; Department of Otolaryngology, The Johns Hopkins University, Baltimore, Maryland, United States of America ^aff003; Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America ^aff004; Department of Biostatistics, The Johns Hopkins University, Baltimore, Maryland, United States of America ^aff005; Department of Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland, United States of America ^aff006
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227727

Souhrn

We sought to design ubiquitin-proteasome system inhibitors active against solid cancers by targeting ubiquitin receptor RPN13 within the proteasome’s 19S regulatory particle. The prototypic bis-benzylidine piperidone-based inhibitor RA190 is a michael acceptor that adducts Cysteine 88 of RPN13. In probing the pharmacophore, we showed the benefit of the central nitrogen-bearing piperidone ring moiety compared to a cyclohexanone, the importance of the span of the aromatic wings from the central enone-piperidone ring, the contribution of both wings, and that substituents with stronger electron withdrawing groups were more cytotoxic. Potency was further enhanced by coupling of a second warhead to the central nitrogen-bearing piperidone as RA375 exhibited ten-fold greater activity against cancer lines than RA190, reflecting its nitro ring substituents and the addition of a chloroacetamide warhead. Treatment with RA375 caused a rapid and profound accumulation of high molecular weight polyubiquitinated proteins and reduced intracellular glutathione levels, which produce endoplasmic reticulum and oxidative stress, and trigger apoptosis. RA375 was highly active against cell lines of multiple myeloma and diverse solid cancers, and demonstrated a wide therapeutic window against normal cells. For cervical and head and neck cancer cell lines, those associated with human papillomavirus were significantly more sensitive to RA375. While ARID1A-deficiency also enhanced sensitivity 4-fold, RA375 was active against all ovarian cancer cell lines tested. RA375 inhibited proteasome function in muscle for >72h after single i.p. administration to mice, and treatment reduced tumor burden and extended survival in mice carrying an orthotopic human xenograft derived from a clear cell ovarian carcinoma.

Klíčová slova:

Apoptosis – Cancer treatment – Cell binding – Flow cytometry – Luciferase – Ovarian cancer – Proteasomes

Zdroje

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Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties

Souhrn

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