Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Long, Marcus J. C.¹  Lawson, Ann P.²  Baggio, Rick^1,7  Qian, Yu³  Rozhansky, Lior²  Fasci, Domenico⁴  El Oualid, Farid⁵  Weerapana, Eranthie³  Hedstrom, Lizbeth^2,6 

[1] Brandeis Univ, Grad Program Biochem & Biophys, 415 South St, Waltham, MA 02453 USA

[2] Brandeis Univ, Dept Biol, 415 South St, Waltham, MA 02453 USA

[3] Boston Coll, Merkert Chem Ctr, Dept Chem, Chestnut Hill, MA 02467 USA

[4] Sanford Bumham Med Res Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA

[5] UbiQ Bio BV, Sci Pk 408, NL-1098 XH Amsterdam, Netherlands

[6] Brandeis Univ, Dept Chem, 415 South St, Waltham, MA 02453 USA

[7] Bioverativ, Qual Assurance Tech Serv, 225 Second Ave, Waltham, MA 02451 USA

关键词: Activity profiling;    USP7;    USP9;    Bcr Abl;    Mdm2;   

DOI  :  10.1016/j.bmcl.2018.11.055

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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