8OUS

CRYSTAL STRUCTURE OF DLK IN COMPLEX WITH COMPOUND 19

8OUS の概要

• エントリーDOI: 10.2210/pdb8ous/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase 12, (1S)-1-[4-[6-azanyl-5-(trifluoromethyloxy)pyridin-3-yl]-1-(3-morpholin-4-yl-1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2-methyl-propan-1-ol (3 entities in total)
• 機能のキーワード: dlk, kinase, inhibitor, signaling protein, transferase-inhibitor, m3k12
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34485.52

構造登録者

Zebisch, M.,McEwan, P.A.,Barker, J.J.,Cross, J.B. (登録日: 2023-04-24, 公開日: 2023-07-26, 最終更新日: 2024-06-19)

主引用文献

Le, K.,Soth, M.J.,Cross, J.B.,Liu, G.,Ray, W.J.,Ma, J.,Goodwani, S.G.,Acton, P.J.,Buggia-Prevot, V.,Akkermans, O.,Barker, J.,Conner, M.L.,Jiang, Y.,Liu, Z.,McEwan, P.,Warner-Schmidt, J.,Xu, A.,Zebisch, M.,Heijnen, C.J.,Abrahams, B.,Jones, P.
Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy.
J.Med.Chem., 66:9954-9971, 2023

PubMed Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 () showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

PubMed: 37436942
DOI: 10.1021/acs.jmedchem.3c00788

実験手法

X-RAY DIFFRACTION (2.2 Å)