8AOP

Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with compound 14r

Summary for 8AOP

• Entry DOI: 10.2210/pdb8aop/pdb
• Descriptor: Cereblon isoform 4, ZINC ION, (3S)-3-[(3-aminophenyl)sulfanylmethyl]piperidine-2,6-dione, ... (5 entities in total)
• Functional Keywords: proteolysis targeting chimera, protac, protein degradation, signaling protein
• Biological source: Magnetospirillum gryphiswaldense MSR-1
• Total number of polymer chains: 3
• Total formula weight: 41784.30

Authors

Maiwald, S.,Heim, C.,Hartmann, M.D. (deposition date: 2022-08-08, release date: 2023-01-11, Last modification date: 2024-02-07)

Primary citation

Krasavin, M.,Adamchik, M.,Bubyrev, A.,Heim, C.,Maiwald, S.,Zhukovsky, D.,Zhmurov, P.,Bunev, A.,Hartmann, M.D.
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., 246:114990-114990, 2023

PubMed 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.

PubMed: 36476642
DOI: 10.1016/j.ejmech.2022.114990

Experimental method

X-RAY DIFFRACTION (1.944 Å)