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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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
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author Krasavin, Mikhail
Bubyrev, Andrey
Kazantsev, Alexander
Heim, Christopher
Maiwald, Samuel
Zhukovsky, Daniil
Dar’in, Dmitry
Hartmann, Marcus D.
Bunev, Alexander
author_facet Krasavin, Mikhail
Bubyrev, Andrey
Kazantsev, Alexander
Heim, Christopher
Maiwald, Samuel
Zhukovsky, Daniil
Dar’in, Dmitry
Hartmann, Marcus D.
Bunev, Alexander
author_sort Krasavin, Mikhail
collection PubMed
description 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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spelling pubmed-88905522022-03-03 Replacing the phthalimide core in thalidomide with benzotriazole Krasavin, Mikhail Bubyrev, Andrey Kazantsev, Alexander Heim, Christopher Maiwald, Samuel Zhukovsky, Daniil Dar’in, Dmitry Hartmann, Marcus D. Bunev, Alexander J Enzyme Inhib Med Chem Short Communication 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. Taylor & Francis 2022-02-28 /pmc/articles/PMC8890552/ /pubmed/35220840 http://dx.doi.org/10.1080/14756366.2021.2024525 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Communication
Krasavin, Mikhail
Bubyrev, Andrey
Kazantsev, Alexander
Heim, Christopher
Maiwald, Samuel
Zhukovsky, Daniil
Dar’in, Dmitry
Hartmann, Marcus D.
Bunev, Alexander
Replacing the phthalimide core in thalidomide with benzotriazole
title Replacing the phthalimide core in thalidomide with benzotriazole
title_full Replacing the phthalimide core in thalidomide with benzotriazole
title_fullStr Replacing the phthalimide core in thalidomide with benzotriazole
title_full_unstemmed Replacing the phthalimide core in thalidomide with benzotriazole
title_short Replacing the phthalimide core in thalidomide with benzotriazole
title_sort replacing the phthalimide core in thalidomide with benzotriazole
topic Short Communication
url 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
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