Discovery of an Inhibitor of the Proteasome Subunit Rpn11.
Basic Information
ID: ALA4049386
Journal: J Med Chem
Title: Discovery of an Inhibitor of the Proteasome Subunit Rpn11.
Authors: Perez C, Li J, Parlati F, Rouffet M, Ma Y, Mackinnon AL, Chou TF, Deshaies RJ, Cohen SM.
Abstract: The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn2+-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation. A fragment-based drug discovery (FBDD) approach was utilized to identify fragments with activity against Rpn11. Screening of a library of metal-binding pharmacophores (MBPs) revealed that 8-thioquinoline (8TQ, IC50 value ∼2.5 μM) displayed strong inhibition of Rpn11. Further synthetic elaboration of 8TQ yielded a small molecule compound (35, IC50 value ∼400 nM) that is a potent and selective inhibitor of Rpn11 that blocks proliferation of tumor cells in culture.
CiteXplore: 28191850
DOI: 10.1021/acs.jmedchem.6b01379
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