The proteasome is a massive proteolytic complex composed of a barrel shaped 20S core protein and one or two capping 19S regulatory protein complexes. It is a major component of the ubiquitin-mediated degradation pathway and plays a crucial role in normal protein degradation required to maintain cell homeostasis. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with the FDA approval of Bortezomib and Carfilzomib. The 19S regulatory complex is composed of multiple distinct subunits that recognize polyubiquitinated proteins as a substrate that become hydrolyzed by the zinc-dependent metalloisopeptidase, Rpn11. The Rpn11 subunit represents an attractive and novel therapeutic target for proteasome inhibition. To this end, we employed a fragment-based drug discovery (FBDD) approach to discover inhibitors of Rpn11. Based on our lead fragment, we prepared a small library of derivatives with in vitro IC<sub>50</sub> values in the nanomolar range.

Metal-binding pharmacophores yields a potent inhibitor of the proteasome subunit Rpn11

251st National Meeting (2016)

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