9HTM

Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with glutarimide based compound 2o

これはPDB形式変換不可エントリーです。

9HTM の概要

• エントリーDOI: 10.2210/pdb9htm/pdb
• 分子名称: Cereblon isoform 4, ZINC ION, (3R)-3-phenylazanylpiperidine-2,6-dione, ... (5 entities in total)
• 機能のキーワード: cereblon, ubiquitination, e3, molecular glue, signaling protein
• 由来する生物種: Magnetospirillum gryphiswaldense
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 41919.63

構造登録者

Bischof, L.,Hartmann, M.D. (登録日: 2024-12-19, 公開日: 2025-10-29)

主引用文献

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

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: 41086529
DOI: 10.1016/j.ejmech.2025.118235

実験手法

X-RAY DIFFRACTION (1.85 Å)