Discovery of an Inhibitor of the Proteasome Subunit Rpn11.

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 ?M) 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.

SUBMITTER: Perez C 

PROVIDER: S-EPMC5761724 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature