Author: Zhuang, Zhihao ; Simeonov, Anton ; Jain, Sankalp ; Baljinnyam, Bolormaa ; Zakharov, Alexey V. ; Doleschal, Megan N. ; Rai, Ganesha ; Miller, Jenna

Ubiquitination is a post-translational modification that elicits a variety of cellular responses. Deubiquitinases (DUBs) remove ubiquitin moieties from proteins and modulate cellular processes by counteracting the ubiquitin ligase activities. Ubiquitination and deubiquitination processes are tightly regulated by different mechanisms and their dysregulation is associated with many diseases. Discovery of DUB inhibitors could not only lead to therapeutics but also facilitate the understanding of ubiquitination/deubiquitination processes and their regulatory mechanisms. To enable the inhibitor discovery against DUBs, we developed a cell-based DUB assay that utilizes a cell-permeable ubiquitin probe, Biotin-cR₁₀-Ub-PA, to covalently label DUBs in their native cellular environment. Amplified luminescent proximity homogeneous assay (Alpha, specifically AlphaLISA) is utilized to quantitatively assess the capture of the target DUB by the Biotin-cR₁₀-Ub-PA probe. We demonstrated that this new cell-based DUB assay is robust and amenable to high-throughput screening. Human USP15 was selected as a DUB of interest and screened against a library of protease inhibitors as a proof of concept. In addition to the widely adopted pan-DUB inhibitor PR-619, several other DUB inhibitors from the library were also identified as hits. This new DUB assay can be readily adapted for inhibitor discovery against many other human DUBs to identify potent and cell-permeable inhibitors.

01 Jan 2019·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor

Q4 · MEDICINE

Article

Author: El Oualid, Farid ; Lawson, Ann P ; Weerapana, Eranthie ; Baggio, Rick ; Hedstrom, Lizbeth ; Qian, Yu ; Long, Marcus J C ; Rozhansky, Lior ; Fasci, Domenico

Promiscuous inhibitors of tyrosine protein kinases, proteases and phosphatases are useful reagents for probing regulatory pathways and stabilizing lysates as well as starting points for the design of more selective agents. Ubiquitination regulates many critical cellular processes, and promiscuous inhibitors of deubiquitinases (DUBs) would be similarly valuable. The currently available promiscuous DUB inhibitors are highly reactive electrophilic compounds that can crosslink proteins. Herein we introduce diarylcarbonate esters as a novel class of promiscuous DUB inhibitors that do not have the liabilities associated with the previously reported compounds. Diarylcarbonates stabilize the high molecular weight ubiquitin pools in cells and lysates. They also elicit cellular phenotypes associated with DUB inhibition, demonstrating their utility in ubiquitin discovery. Diarylcarbonates may also be a useful scaffold for the development of specific DUB inhibitors.

Molecular glues that inhibit specific Zn2+-dependent DUB activity and inflammation

Article

Author: Walden, Miriam ; Calabrese, Antonio N. ; Aman, Ahmed ; Calabrese, Antonio N ; Salvino, Joseph M ; Cassel, Joel A. ; Greenberg, Roger A ; Bhutda, Smita ; Bell, Lillie ; Prakesch, Michael A ; Salvino, Joseph M. ; Ross, Rebecca L ; Ross, Rebecca L. ; Reddy, Poli Adi Narayana ; Sicheri, Frank ; Datti, Alessandro ; Prakesch, Michael A. ; Al-awar, Rima S. ; Campbell, Lisa J. ; Stein, Daniel N. ; Cassel, Joel A ; Zeqiraj, Elton ; Foglizzo, Martina ; Chandler, Francesca ; Stein, Daniel N ; Del Galdo, Francesco ; Walker, Kieran ; Ault, James R. ; Di Donato, Stefano ; Greenberg, Roger A. ; Al-Awar, Rima S ; Campbell, Lisa J ; Ault, James R

Deubiquitylases (DUBs) play a pivotal role in cell signalling and are often regulated by homo- or hetero-interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by selectively cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). BRCC36 is a Zn2+-dependent JAMM/MPN DUB, a challenging ubiquitin protease class for the design of selective inhibitors. We identified first-in-class DUB inhibitors that act as BRISC molecular glues (BLUEs). BLUEs inhibit DUB activity by stabilising a BRISC dimer consisting of 16 subunits. The BLUE-stabilised BRISC dimer is an autoinhibited conformation, whereby the active sites and interactions with the recruiting subunit SHMT2 are blocked. This unique mode of action leads to highly selective inhibitors for BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. Structure-guided inhibitor resistant mutants confirm BLUEs on-target activity in cells, and BLUE treatment results in reduced interferon-stimulated gene (ISG) expression in human peripheral blood mononuclear cells from Scleroderma patients, a disease linked with aberrant IFNAR1 activation. BLUEs represent a new class of molecules with potential utility in Type I interferon-mediated diseases and a template for designing selective inhibitors of large protein complexes by promoting protein-protein interactions instead of blocking them.

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