8I2N

The RIPK1 kinase domain in complex with QY7-2B compound

8I2N の概要

• エントリーDOI: 10.2210/pdb8i2n/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 1, ~{N}-methyl-1-[4-[[[1-methyl-5-(phenylmethyl)pyrazol-3-yl]carbonylamino]methyl]phenyl]benzimidazole-5-carboxamide (3 entities in total)
• 機能のキーワード: ripk1, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67894.55

構造登録者

Gong, X.Y.,Li, Y.,Meng, H.Y.,Pan, L.F. (登録日: 2023-01-14, 公開日: 2024-01-31, 最終更新日: 2024-08-21)

主引用文献

Qin, Y.,Li, D.,Qi, C.,Xiang, H.,Meng, H.,Liu, J.,Zhou, S.,Gong, X.,Li, Y.,Xu, G.,Zu, R.,Xie, H.,Xu, Y.,Xu, G.,Zhang, Z.,Chen, S.,Pan, L.,Li, Y.,Tan, L.
Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.
Acta Pharm Sin B, 14:319-334, 2024

PubMed Abstract: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, , which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

PubMed: 38261830
DOI: 10.1016/j.apsb.2023.10.021

実験手法

X-RAY DIFFRACTION (2.29 Å)