Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor 
Cereblon (CRBN): Investigation of their binding mode and antiproliferative 
effects against myeloma cell lines

Krasavin, M; Adamchik, M; Bubyrev, A; Heim, C; Maiwald, S; Zhukovsky, D; Zhmurov, P; Bunev, A; Hartmann, MD

doi:10.1016/j.ejmech.2022.114990

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Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN): Investigation of their binding mode and antiproliferative effects against myeloma cell lines

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Heim, C
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;
Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;

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Maiwald, S
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;
Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;

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Hartmann, MD
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;
Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;

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Citation

Krasavin, M., Adamchik, M., Bubyrev, A., Heim, C., Maiwald, S., Zhukovsky, D., et al. (2022). Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN): Investigation of their binding mode and antiproliferative effects against myeloma cell lines. European Journal of Medicinal Chemistry, 246: 114990. doi:10.1016/j.ejmech.2022.114990.

Cite as: https://hdl.handle.net/21.11116/0000-000B-F0CA-2

Abstract

To expand the chemical toolkit for targeted protein degradation, we report the generation of a new series of non-thalidomide Cereblon (CRBN) ligands. Readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides via the thio-Michael addition reaction. The compounds thus synthesized were evaluated for their affinity to the thalidomide-binding domain of human CRBN and their binding modes studied via X-ray crystallography. This helped identify several promising glutarimide derivatives which bind stronger to CRBN compared to thalidomide and contain a functional group which permits further chemical conjugation. Oxidation of the sulfur atom in a select group of 2-((hetero)aryl(methyl))thio glutarimides produced the respective sulfones which were found to possess a markedly stronger antiproliferative profile against multiple myeloma cell lines and a sophisticated structural binding mode with additional hydrogen bonding interactions. The newly identified Cereblon ligands form the basis for the synthesis of novel PROTAC protein degraders.