9HTK
Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with glutarimide based compound 2n
This is a non-PDB format compatible entry.
Summary for 9HTK
| Entry DOI | 10.2210/pdb9htk/pdb |
| Descriptor | Cereblon isoform 4, ZINC ION, (3S)-3-phenylsulfanylpiperidine-2,6-dione, ... (5 entities in total) |
| Functional Keywords | cereblon, ubiquitination, e3, molecular glue, signaling protein |
| Biological source | Magnetospirillum gryphiswaldense |
| Total number of polymer chains | 3 |
| Total formula weight | 41970.79 |
| Authors | |
| Primary citation | Levashova, E.,Bischof, L.,Bunev, A.,Sapegin, A.,Grygor'eva, O.,Kudinov, A.,Ebeling, S.,Tatarinov, I.,Dar'in, D.,Kantin, G.,Hartmann, M.D.,Kalinin, S. Extending the chemical space of glutarimide-based cereblon ligands through an efficient Rh(II)-catalyzed X-H insertion reaction. Eur.J.Med.Chem., 301:118235-118235, 2025 Cited by PubMed Abstract: In this work we present an easy, one-step synthetic protocol to explore a large chemical space of glutarimide-based cereblon (CRBN) ligands for targeted protein degradation. It is built upon our recently suggested approach to generating structurally diverse series of alpha-substituted glutarimide derivatives through an efficient Rh(II)-catalyzed X-H insertion reaction of 3-diazopiperidine-2,6-dione, with moderate to high yields. In total, 25 glutarimide derivatives incorporating variable side chains were synthesized and evaluated in vitro. All ligands showed a favorable lipophilicity, and several were able to outperform the binding affinity of thalidomide as a reference. In addition, most compounds showed low intrinsic cytotoxicity in myeloma cell lines and human peripheral blood mononuclear cells, and did not recruit canonical neosubstrates. A cellular thermal shift assay further demonstrated that the most potent analogs stabilize CRBN in live cells, confirming their on-target engagement. The development of the series was accompanied by a crystallographic study, which rationalizes the observed improvements in binding affinity and neosubstrate selectivity, and can support further development towards molecular glue activity and PROTACs design. PubMed: 41086529DOI: 10.1016/j.ejmech.2025.118235 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.49 Å) |
Structure validation
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