2024
DOI: 10.1002/anie.202318849
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N‐Cyanopiperazines as Specific Covalent Inhibitors of the Deubiquitinating Enzyme UCHL1

Mirko Schmidt,
Christian Grethe,
Sarah Recknagel
et al.

Abstract: Cyanamides have emerged as privileged scaffolds in covalent inhibitors of deubiquitinating enzymes (DUBs). However, many compounds with a cyanopyrrolidine warhead show cross‐reactivity toward small subsets of DUBs or toward the protein deglycase PARK7/DJ‐1, hampering their use for the selective perturbation of a single DUB in living cells. Here, we disclose N’‐alkyl,N‐cyanopiperazines as structures for covalent enzyme inhibition with exceptional specificity for the DUB UCHL1 among 55 human deubiquitinases and … Show more

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Cited by 4 publications
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“…The reason for the disagreement between the fluorescent labeling and SLC-ABPP experiments could be due to the changes in the chemical composition of JYQ-173 by installment of dye as the similar effect observed in the previous studies for UCHL1-selective probes. 17 , 18 , 43 Previously, Sieber and co-workers reported an alkyne-equipped probe to monitor PARK7 in different cell lines after a postlysis click reaction with rhodamine- or biotin-azide. 14 The presented probes here provide great advantages because of the highly efficient one-step labeling of cellular PARK7 without a need for an intermediate click chemistry reaction, thus omitting all disadvantages associated with two-step labeling.…”
Section: Discussionmentioning
confidence: 99%
“…The reason for the disagreement between the fluorescent labeling and SLC-ABPP experiments could be due to the changes in the chemical composition of JYQ-173 by installment of dye as the similar effect observed in the previous studies for UCHL1-selective probes. 17 , 18 , 43 Previously, Sieber and co-workers reported an alkyne-equipped probe to monitor PARK7 in different cell lines after a postlysis click reaction with rhodamine- or biotin-azide. 14 The presented probes here provide great advantages because of the highly efficient one-step labeling of cellular PARK7 without a need for an intermediate click chemistry reaction, thus omitting all disadvantages associated with two-step labeling.…”
Section: Discussionmentioning
confidence: 99%