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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Perez C,Li J,Parlati F,Rouffet M,Ma Y,Mackinnon AL,Chou TF,Deshaies RJ,Cohen SMdoi
10.1021/acs.jmedchem.6b01379subject
Has Abstractpub_date
2017-02-23 00:00:00pages
1343-1361issue
4eissn
0022-2623issn
1520-4804journal_volume
60pub_type
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