Replacing the phthalimide core in thalidomide with benzotriazole

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 rec...

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Detalles Bibliográficos
Autores principales: Krasavin, Mikhail, Bubyrev, Andrey, Kazantsev, Alexander, Heim, Christopher, Maiwald, Samuel, Zhukovsky, Daniil, Dar’in, Dmitry, Hartmann, Marcus D., Bunev, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Short Communication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890552/
https://www.ncbi.nlm.nih.gov/pubmed/35220840
http://dx.doi.org/10.1080/14756366.2021.2024525
Descripción
Sumario: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 CRL4A(CRBN) 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 crystallographic analyses, affinity assays and cell culture.

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