학술논문
Replacing the phthalimide core in thalidomide with benzotriazole.
Document Type
Article
Author
Source
Subject
*THALIDOMIDE
*BENZOTRIAZOLE
*UBIQUITIN ligases
*CELL culture
*LIGASES
*DIAZO compounds
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Language
ISSN
1475-6366
Abstract
The advent of proteolysis-targeting chimaeras (PROTACs) mandates that new ligands for the recruitment of E3 ligases are discovered. The traditional immunomodulatory drugs (IMiDs) such as thalidomide and its analogues (all based on the phthalimide glutarimide core) bind to Cereblon, the substrate receptor of the CRL4ACRBN E3 ligase. We designed a thalidomide analogue in which the phthalimide moiety was replaced with benzotriazole, using an innovative synthesis strategy. Compared to thalidomide, the resulting "benzotriazolo thalidomide" has a similar binding mode, but improved properties, as revealed in crystallo-graphic analyses, affinity assays and cell culture. [ABSTRACT FROM AUTHOR]