4I6H
Selective & Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors that Reduce alpha-Synuclein Phosphorylation in Rat Brain
Summary for 4I6H
| Entry DOI | 10.2210/pdb4i6h/pdb |
| Related | 4I6B 4I6F |
| Descriptor | Serine/threonine-protein kinase PLK2, (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2-(1,3-thiazol-4-yl)-1H-imidazol-1-yl]-7,8-dihydropteridin-6(5H)-one (3 entities in total) |
| Functional Keywords | parkinson s disease, kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole: Q9NYY3 |
| Total number of polymer chains | 1 |
| Total formula weight | 36241.70 |
| Authors | |
| Primary citation | Aubele, D.L.,Hom, R.K.,Adler, M.,Galemmo, R.A.,Bowers, S.,Truong, A.P.,Pan, H.,Beroza, P.,Neitz, R.J.,Yao, N.,Lin, M.,Tonn, G.,Zhang, H.,Bova, M.P.,Ren, Z.,Tam, D.,Ruslim, L.,Baker, J.,Diep, L.,Fitzgerald, K.,Hoffman, J.,Motter, R.,Fauss, D.,Tanaka, P.,Dappen, M.,Jagodzinski, J.,Chan, W.,Konradi, A.W.,Latimer, L.,Zhu, Y.L.,Sham, H.L.,Anderson, J.P.,Bergeron, M.,Artis, D.R. Selective & Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors that Reduce alpha-Synuclein Phosphorylation in Rat Brain Chemmedchem, 8:1295-1313, 2013 Cited by PubMed Abstract: Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease. PubMed: 23794260DOI: 10.1002/cmdc.201300166 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.91 Å) |
Structure validation
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