Replacing the phthalimide core in thalidomide with benzotriazole |
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| Authors: | Mikhail Krasavin Andrey Bubyrev Alexander Kazantsev Christopher Heim Samuel Maiwald Daniil Zhukovsky Dmitry Dar&#x;in Marcus D Hartmann Alexander Bunev |
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| Institution: | aInstitute of Chemistry, Saint Petersburg State University, Saint Petersburg, Russia;bDepartment of Protein Evolution, Max Planck Institute for Developmental Biology, Tübingen, Germany;cMedicinal Chemistry Center, Togliatti State University, Togliatti, Russia |
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| 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 crystallographic analyses, affinity assays and cell culture. |
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| Keywords: | Cereblon immunomodulatory drugs phthalimide benzotriazole diazo compounds carbene N-H insertion |
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