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 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.
Additional Information
© 2017 American Chemical Society. Received: September 20, 2016; Published: February 13, 2017. We acknowledge Dr. Yongxuan Su (U.C. San Diego Molecular Mass Spectrometry Facility) for aid with HR-MS and HPLC fragment purity analysis. We acknowledge Dr. Dave P. Martin and Dr. David T. Puerta for their helpful discussions and assistance with the synthesis and characterization of the [(Tp^(Me,Ph))Zn(8TQ)] metal complex and the U.C. San Diego X-ray diffraction facilities for assistance with experiments. We also thank Dr. Elton Zeqiraj for providing purified BRISC complex. This work was initiated with an American Recovery and Reinvestment Act (ARRA) supplement to R.J.D. (3-R01-GM065997–07S1), followed by a grant to S.M.C. and R.J.D. from the National Cancer Institute (R01-CA164803). J.L. was supported in part by a Caltech Grubstake Award and CBEA Award from Amgen. R.J.D. is an Investigator of the Howard Hughes Medical Institute and this work was supported in part by HHMI.Errata
Page 1343. The author list and author affiliations should be modified to include a new author Han-Jie Zhou of Cleave Biosciences. The correct author listing is shown above, and the correct author listing with the affiliation symbols and the associated affiliations are shown below. Note that nonaffiliation symbols in the author listing below are defined in the manuscript.Attached Files
Accepted Version - nihms930851.pdf
Supplemental Material - jm6b01379_si_001.pdf
Supplemental Material - jm6b01379_si_002.csv
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Additional details
- PMCID
- PMC5761724
- Eprint ID
- 75381
- Resolver ID
- CaltechAUTHORS:20170324-090339100
- American Recovery and Reinvestment Act (ARRA)
- 3-R01-GM065997-07S1
- NIH
- R01-CA164803
- NIH
- Caltech Grubstake Fund
- Amgen
- Howard Hughes Medical Institute (HHMI)
- National Cancer Institute
- Created
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2017-03-24Created from EPrint's datestamp field
- Updated
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2022-04-06Created from EPrint's last_modified field