2. Academic Validation
  3. Discovery of Highly Selective Inhibitors of the Human Constitutive Proteasome β5c Chymotryptic Subunit

Discovery of Highly Selective Inhibitors of the Human Constitutive Proteasome β5c Chymotryptic Subunit

  • J Med Chem. 2023 Jan 26;66(2):1172-1185. doi: 10.1021/acs.jmedchem.2c00733.
Wenhu Zhan 1,  Daqiang Li 1,  Priya Saha 1,  Rong Wang 2,  Hao Zhang 1,  Amrendra K Ajay 3,  Christa Deban 4,  George Sukenick 2,  Jamil Azzi 3,  Gang Lin 1
Affiliations

Affiliations

  • 1 Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Ave., New York, New York 10065, United States.
  • 2 NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 3 Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 4 Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 36608337 DOI: 10.1021/acs.jmedchem.2c00733
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.

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