2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2023 Jan 15:246:114990. doi: 10.1016/j.ejmech.2022.114990.
Mikhail Krasavin 1,  Maria Adamchik 2,  Andrey Bubyrev 2,  Christopher Heim 3,  Samuel Maiwald 4,  Daniil Zhukovsky 2,  Petr Zhmurov 2,  Alexander Bunev 5,  Marcus D Hartmann 6
Affiliations

Affiliations

  • 1 Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation; Immanuel Kant Baltic Federal University, Kaliningrad, 236041, Russian Federation. Electronic address: [email protected].
  • 2 Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation.
  • 3 Department of Protein Evolution, Max Planck Institute for Biology, Tübingen, Germany; Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
  • 4 Department of Protein Evolution, Max Planck Institute for Biology, Tübingen, Germany.
  • 5 Medicinal Chemistry Center, Togliatti State University, Togliatti, 445020, Russian Federation.
  • 6 Department of Protein Evolution, Max Planck Institute for Biology, Tübingen, Germany; Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany. Electronic address: [email protected].
PMID: 36476642 DOI: 10.1016/j.ejmech.2022.114990
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.

Keywords

Cereblon; IMiDs; Molecular glue; New ligand space; PROTAC; Thio-Michael addition.

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