7SUH
Structure of CHK1 10-pt. mutant complex with LRRK2 inhibitor 15
Summary for 7SUH
| Entry DOI | 10.2210/pdb7suh/pdb |
| Descriptor | Serine/threonine-protein kinase Chk1, 1-[5-chloro-4-({6-chloro-7-[1-(oxetan-3-yl)piperidin-4-yl]quinazolin-2-yl}amino)-1H-pyrazol-1-yl]-2-methylpropan-2-ol (3 entities in total) |
| Functional Keywords | kinase, parkinson's disease, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 34585.62 |
| Authors | Palte, R.L. (deposition date: 2021-11-17, release date: 2022-01-12, Last modification date: 2023-10-18) |
| Primary citation | 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 Cited by 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: 34967623DOI: 10.1021/acs.jmedchem.1c01968 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.46 Å) |
Structure validation
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