6PM9
Crystal structure of the core catalytic domain of human O-GlcNAcase bound to MK-8719
Summary for 6PM9
| Entry DOI | 10.2210/pdb6pm9/pdb |
| Descriptor | 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) |
| Functional Keywords | hydrolase, o-glcnacase, gh84, inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 8 |
| Total formula weight | 250691.40 |
| Authors | Klein, D.J.,Selnick, H.G.,Duffy, J.L.,McEachern, E.J. (deposition date: 2019-07-01, release date: 2019-09-18, Last modification date: 2024-03-13) |
| Primary citation | 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 Cited by 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: 31487175DOI: 10.1021/acs.jmedchem.9b01090 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.86 Å) |
Structure validation
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