7SUF

Structure of CHK1 10-pt. mutant complex with LRRK2 inhibitor 06

7SUF の概要

• エントリーDOI: 10.2210/pdb7suf/pdb
• 分子名称: Serine/threonine-protein kinase Chk1, 8-cyclopropyl-N-[5-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]quinazolin-2-amine, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: kinase, parkinson's disease, transferase-transferase inhibitor complex, transferase/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: 34691.91

構造登録者

Palte, R.L. (登録日: 2021-11-17, 公開日: 2022-01-12, 最終更新日: 2023-10-18)

主引用文献

Keylor, M.H.,Gulati, A.,Kattar, S.D.,Johnson, R.E.,Chau, R.W.,Margrey, K.A.,Ardolino, M.J.,Zarate, C.,Poremba, K.E.,Simov, V.,Morriello, G.J.,Acton, J.J.,Pio, B.,Yan, X.,Palte, R.L.,McMinn, S.E.,Nogle, L.,Lesburg, C.A.,Adpressa, D.,Lin, S.,Neelamkavil, S.,Liu, P.,Su, J.,Hegde, L.G.,Woodhouse, J.D.,Faltus, R.,Xiong, T.,Ciaccio, P.J.,Piesvaux, J.,Otte, K.M.,Wood, H.B.,Kennedy, M.E.,Bennett, D.J.,DiMauro, E.F.,Fell, M.J.,Fuller, P.H.
Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.
J.Med.Chem., 65:838-856, 2022

PubMed Abstract: The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds and . These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

PubMed: 34967623
DOI: 10.1021/acs.jmedchem.1c01968

実験手法

X-RAY DIFFRACTION (1.48 Å)