9CE4

Structure of CHK1 10-pt. mutant complex with LRRK2 indazole inhibitor compound 6

これはPDB形式変換不可エントリーです。

9CE4 の概要

• エントリーDOI: 10.2210/pdb9ce4/pdb
• 分子名称: Serine/threonine-protein kinase Chk1, (1S,4r)-4-[(1P)-5-chloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl]-1-(oxetan-3-yl)piperidin-1-ium, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: kinase, parkinson's disease, lrrk2, transferase
• 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: 31781.12

構造登録者

Palte, R.L.,Zebisch, M.,Henry, C.,Barker, J.J. (登録日: 2024-06-26, 公開日: 2024-09-18, 最終更新日: 2024-10-02)

主引用文献

Logan, K.M.,Kaplan, W.,Simov, V.,Zhou, H.,Li, D.,Torres, L.,Morriello, G.J.,Acton, J.J.,Pio, B.,Chen, Y.H.,Keylor, M.H.,Johnson, R.,Kattar, S.D.,Chau, R.,Yan, X.,Ardolino, M.,Zarate, C.,Otte, K.M.,Palte, R.L.,Xiong, T.,McMinn, S.E.,Lin, S.,Neelamkavil, S.F.,Liu, P.,Su, J.,Hegde, L.G.,Woodhouse, J.D.,Moy, L.Y.,Ciaccio, P.J.,Piesvaux, J.,Zebisch, M.,Henry, C.,Barker, J.,Wood, H.B.,Kennedy, M.E.,DiMauro, E.F.,Fell, M.J.,Fuller, P.H.
Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors.
J.Med.Chem., 67:16807-16819, 2024

PubMed Abstract: Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment of Parkinson's disease. We previously disclosed the discovery of an indazole series lead that demonstrated both safety and translational risks. The safety risks were hypothesized to be of unknown origin, so structural diversity in subsequent chemical matter was prioritized. The translational risks were identified due to a low brain Kp in nonhuman primate studies, which raised concern over the use of an established peripheral biomarker as a surrogate for central target engagement. Given these challenges, the team sought to leverage structure- and property-based drug design and expanded efflux transporter profiling to identify structurally distinct leads with enhanced CNS drug-likeness. Herein, we describe the discovery of a "reinvented" indazole series with improved physicochemical properties and efflux transporter profiles while maintaining excellent potency and off-target kinase selectivity, which resulted in advanced lead, compound .

PubMed: 39231262
DOI: 10.1021/acs.jmedchem.4c01627

実験手法

X-RAY DIFFRACTION (1.31 Å)