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Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties
- Source :
- PLoS ONE, PLoS ONE, Vol 15, Iss 1, p e0227727 (2020)
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Treatment
Apoptosis
Biochemistry
Plasma Cell Disorders
Hematologic Cancers and Related Disorders
Mice
0302 clinical medicine
Spectrum Analysis Techniques
Ubiquitin
Neoplasms
Medicine and Health Sciences
Receptor
Multidisciplinary
biology
Molecular Structure
Cell Death
Chemistry
Intracellular Signaling Peptides and Proteins
Hematology
Flow Cytometry
Small molecule
Ubiquitinated Proteins
3. Good health
Ovarian Cancer
Enzymes
Myelomas
Oncology
Cell Processes
Spectrophotometry
030220 oncology & carcinogenesis
Medicine
Female
Cytophotometry
Pharmacophore
Multiple Myeloma
Oxidoreductases
Proteasome Inhibitors
Luciferase
Protein Binding
Research Article
Cell Binding
Proteasome Endopeptidase Complex
Cell Physiology
Science
Antineoplastic Agents
Research and Analysis Methods
Benzylidene Compounds
03 medical and health sciences
Inhibitory Concentration 50
Structure-Activity Relationship
Cell Line, Tumor
medicine
Structure–activity relationship
Animals
Humans
Myelomas and Lymphoproliferative Diseases
Ubiquitination
Cancer
Biology and Life Sciences
Proteins
Protein Complexes
Proteasomes
Cancers and Neoplasms
Cell Biology
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
Proteasome
Cancer research
biology.protein
Enzymology
Gynecological Tumors
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 15
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....b6f701592cd645b23744d8543ee93f3d