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 Rpnll. Screening of a library of metal-binding pharmacophores (MBPs) revealed that 8-thioquinoline (8TQ IC50 value similar to 2.5 mu M) displayed strong inhibition of Rpn11. Further synthetic elaboration of 8TQyielded a small molecule compound (35, IC50 value similar to 400 nM) that is a potent and selective inhibitor of Rpn11 that blocks proliferation of tumor cells in culture.
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