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


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: 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 – Multiple myeloma – Ovarian cancer – Proteasomes


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