Discovery of highly selective inhibitors of the human constitutive proteasome β5c chymotryptic subunit Journal Article
| Authors: | Zhan, W.; Li, D.; Saha, P.; Wang, R.; Zhang, H.; Ajay, A. K.; Deban, C.; Sukenick, G.; Azzi, J.; Lin, G. |
| Article Title: | Discovery of highly selective inhibitors of the human constitutive proteasome β5c chymotryptic subunit |
| Abstract: | We describe our discovery and development of potent and highly selective inhibitors of human constitutive proteasome chymotryptic activity (β5c). Structure-activity relationship studies of the novel class of inhibitors focused on optimization of N-cap, C-cap, and side chain of the chemophore asparagine. Compound 32 is the most potent and selective β5c inhibitor in this study. A docking study provides a structure rationale for potency and selectivity. Kinetic studies show a reversible and noncompetitive inhibition mechanism. It enters the cells to engage the proteasome target, potently and selectively kills multiple myeloma cells, and does so by synergizing with a β5i-selective inhibitor. © 2023 American Chemical Society. |
| Keywords: | metabolism; proteasome; proteasome inhibitor; proteasome endopeptidase complex; structure activity relation; structure-activity relationship; chemistry; kinetics; asparagine; proteasome inhibitors; humans; human |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 66 |
| Issue: | 2 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2023-01-26 |
| Start Page: | 1172 |
| End Page: | 1185 |
| Language: | English |
| DOI: | 10.1021/acs.jmedchem.2c00733 |
| PUBMED: | 36608337 |
| PROVIDER: | scopus |
| PMCID: | PMC10157300 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in PubMed and PDF -- Source: Scopus |
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