9CUO

Crystal structure of CRBN with compound 3

これはPDB形式変換不可エントリーです。

9CUO の概要

• エントリーDOI: 10.2210/pdb9cuo/pdb
• 分子名称: Protein cereblon, ZINC ION, (3S)-3-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidine-2,6-dione, ... (6 entities in total)
• 機能のキーワード: crbn, e3, protein degradation, ligase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 79190.35

構造登録者

Zheng, X.,Ji, N.,Campbell, V.,Slavin, A.,Zhu, X.,Chen, D.,Rong, H.,Enerson, B.,Mayo, M.,Sharma, K.,Browne, C.M.,Klaus, C.R.,Li, H.,Massa, G.,McDonald, A.A.,Shi, Y.,Sintchak, M.,Skouras, S.,Walther, D.M.,Yuan, K.,Zhang, Y.,Kelleher, J.,Guang, L.,Luo, X.,Mainolfi, N.,Weiss, M.M. (登録日: 2024-07-26, 公開日: 2024-08-28, 最終更新日: 2024-11-06)

主引用文献

Zheng, X.,Ji, N.,Campbell, V.,Slavin, A.,Zhu, X.,Chen, D.,Rong, H.,Enerson, B.,Mayo, M.,Sharma, K.,Browne, C.M.,Klaus, C.R.,Li, H.,Massa, G.,McDonald, A.A.,Shi, Y.,Sintchak, M.,Skouras, S.,Walther, D.M.,Yuan, K.,Zhang, Y.,Kelleher, J.,Liu, G.,Luo, X.,Mainolfi, N.,Weiss, M.M.
Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases.
J.Med.Chem., 67:18022-18037, 2024

PubMed Abstract: Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an attractive approach for the treatment of autoimmune diseases. The activity of this serine/threonine kinase is dependent on its kinase and scaffolding activities; thus, degradation represents a potentially superior approach to inhibition. Herein, we detail the exploration of structure-activity relationships that ultimately led to the identification of KT-474, a potent, selective, and orally bioavailable heterobifunctional IRAK4 degrader. This represents the first heterobifunctional degrader evaluated in a nononcology indication and dosed to healthy human volunteers. This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.

PubMed: 39151120
DOI: 10.1021/acs.jmedchem.4c01305

実験手法

X-RAY DIFFRACTION (1.6 Å)