Discovery of an Inhibitor of the Proteasome Subunit Rpn11

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.