9CE4
Structure of CHK1 10-pt. mutant complex with LRRK2 indazole inhibitor compound 6
This is a non-PDB format compatible entry.
Summary for 9CE4
| Entry DOI | 10.2210/pdb9ce4/pdb |
| Descriptor | 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) |
| Functional Keywords | kinase, parkinson's disease, lrrk2, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 31781.12 |
| Authors | Palte, R.L.,Zebisch, M.,Henry, C.,Barker, J.J. (deposition date: 2024-06-26, release date: 2024-09-18, Last modification date: 2024-10-02) |
| Primary citation | 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 Cited by 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: 39231262DOI: 10.1021/acs.jmedchem.4c01627 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.31 Å) |
Structure validation
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