10IA

Structure of CHK1 10-pt. mutant complex with macrocyclic LRRK2 inhibitor compound 12 ((10aS,13aS)-3-cyclopropyl-1-methyl-8-(trifluoromethyl)-3,4,10a,11,13a,14-hexahydro-10H,13H-9,5-(azeno)furo[3,4-k]pyrazolo[4,3-b][1,4,6,10]oxatriazacyclotridecine)

これはPDB形式変換不可エントリーです。

10IA の概要

• エントリーDOI: 10.2210/pdb10ia/pdb
• 分子名称: Serine/threonine-protein kinase Chk1, (10aS,13aS)-3-cyclopropyl-1-methyl-8-(trifluoromethyl)-3,4,10a,11,13a,14-hexahydro-10H,13H-9,5-(azeno)furo[3,4-k]pyrazolo[4,3-b][1,4,6,10]oxatriazacyclotridecine (3 entities in total)
• 機能のキーワード: lrrk2, parkinson's, kinase, transferase-inhibitor complex, transferase/inhibitor
• 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: 34490.57

構造登録者

Palte, R.L.,Yu, E.C.,Zhou, H. (登録日: 2026-01-21, 公開日: 2026-04-08)

主引用文献

Yu, E.C.,Zhou, H.,Yan, X.,Logan, K.M.,Li, D.,Gulati, A.,Poremba, K.E.,Ardolino, M.J.,Su, J.,Xiao, D.,Palte, R.L.,McMinn, S.E.,Nogle, L.M.,Adpressa, D.A.,Burgess, S.A.,Xiong, T.,Otte, K.M.,Chobanian, H.R.,Bass, A.,Lee, S.,Pearson, K.,Messina, E.,Parisi, M.,Barnum, J.,Sobol, Z.,Ciaccio, P.J.,DiMauro, E.F.,Fell, M.J.,Fuller, P.H.
Discovery of Potent, Selective, CNS-Penetrant Macrocyclic LRRK2 Inhibitors for the Treatment of Parkinson's Disease.
J.Med.Chem., 2026

PubMed Abstract: Genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder for which treatments are limited. Herein, we describe the invention of a macrocyclic LRRK2 inhibitor lead chemical series. Rigorous application of knowledge-, structure-, and property-based drug design culminated in the discovery of compound , which was profiled extensively before it was determined to be clastogenic, which halted its progression. Parallel optimization of kinome selectivity and PXR activation through structure- and property-based drug design resulted in the discovery of the lead macrocycle compound . This macrocycle boasts a remarkably low projected human QD dose, is nongenotoxic, and achieved encouraging brain penetration in early preclinical models.

PubMed: 41906303
DOI: 10.1021/acs.jmedchem.6c00238

実験手法

X-RAY DIFFRACTION (1.739 Å)