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Halogen Substituents in the Isoquinoline Scaffold Switches the Selectivity of Inhibition between USP2 and USP7
Author(s) -
Vamisetti Ganga B.,
Meledin Roman,
Gopinath Pushparathinam,
Brik Ashraf
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800612
Subject(s) - isoquinoline , chemistry , deubiquitinating enzyme , combinatorial chemistry , halogen , selectivity , drug discovery , lead compound , halogen bond , stereochemistry , biochemistry , in vitro , organic chemistry , ubiquitin , gene , alkyl , catalysis
Deubiquitinases are important components of the protein regulatory network and, hence, constitute a tempting drug target. We report herein structure–activity relationship studies to develop halogen‐substituted isoquionoline‐1,3‐dione‐based inhibitors of the deubiquitinase USP2. In contrast to our previous reports, the best compound discovered was found to act through a reactive oxygen species independent, uncompetitive mechanism with an IC 50 of 250 n m . We show the crucial role of halogens in the common scaffold to provide potency and selectivity of our compound, where the introduction of the fluorine atom completely switches the selectivity of the inhibitor between USP2 and USP7. Our cellular studies highlight the potential applicability of the reported compound for in vivo experiments. The discovery of the isoquinoline‐1,3‐dione core and the knowledge obtained with regard to halogen substituents provide a platform towards understanding USP2 inhibition and the development of highly selective next‐generation deubiquitinase inhibitors.