Summary for 9CDY
| Entry DOI | 10.2210/pdb9cdy/pdb |
| Descriptor | Mitogen-activated protein kinase kinase kinase 12, 3-{(3M)-3-[6-amino-5-(trifluoromethoxy)pyridin-3-yl]-1-ethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl}-1,5-anhydro-3,4-dideoxy-2-O-methyl-D-erythro-pentitol, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | inhibitor, complex, dual leucine zipper bearing kinase, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 34557.82 |
| Authors | Skene, R.J.,Bell, J.A. (deposition date: 2024-06-25, release date: 2025-02-19, Last modification date: 2025-02-26) |
| Primary citation | Lagiakos, H.R.,Zou, Y.,Igawa, H.,Therrien, E.,Lawrenz, M.,Kato, M.,Svensson, M.,Gray, F.,Jensen, K.,Dahlgren, M.K.,Pelletier, R.D.,Dingley, K.,Bell, J.A.,Liu, Z.,Jiang, Y.,Zhou, H.,Skene, R.J.,Nie, Z. In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury. J.Med.Chem., 68:2720-2741, 2025 Cited by PubMed Abstract: Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge tools. KAI-11101 displayed an excellent safety profile and showed neuroprotective properties in an axon fragmentation assay as well as dose-dependent activity in a mouse PD model. PubMed: 39670820DOI: 10.1021/acs.jmedchem.4c02074 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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