6PM9

Crystal structure of the core catalytic domain of human O-GlcNAcase bound to MK-8719

6PM9 の概要

• エントリーDOI: 10.2210/pdb6pm9/pdb
• 分子名称: O-GlcNAcase TIM-barrel domain, O-GlcNAcase stalk domain, (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol, ... (4 entities in total)
• 機能のキーワード: hydrolase, o-glcnacase, gh84, inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 250691.40

構造登録者

Klein, D.J.,Selnick, H.G.,Duffy, J.L.,McEachern, E.J. (登録日: 2019-07-01, 公開日: 2019-09-18, 最終更新日: 2024-03-13)

主引用文献

Selnick, H.G.,Hess, J.F.,Tang, C.,Liu, K.,Schachter, J.B.,Ballard, J.E.,Marcus, J.,Klein, D.J.,Wang, X.,Pearson, M.,Savage, M.J.,Kaul, R.,Li, T.S.,Vocadlo, D.J.,Zhou, Y.,Zhu, Y.,Mu, C.,Wang, Y.,Wei, Z.,Bai, C.,Duffy, J.L.,McEachern, E.J.
Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies.
J.Med.Chem., 62:10062-10097, 2019

PubMed Abstract: Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3a,5,6,7,7a)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5-pyrano[3,2-]thiazole-6,7-diol (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.

PubMed: 31487175
DOI: 10.1021/acs.jmedchem.9b01090

実験手法

X-RAY DIFFRACTION (2.86 Å)