4I6H

Selective & Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors that Reduce alpha-Synuclein Phosphorylation in Rat Brain

4I6H の概要

• エントリーDOI: 10.2210/pdb4i6h/pdb
• 関連するPDBエントリー: 4I6B 4I6F
• 分子名称: 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)
• 機能のキーワード: parkinson s disease, kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole: Q9NYY3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36241.70

構造登録者

Pan, H. (登録日: 2012-11-29, 公開日: 2013-08-14, 最終更新日: 2024-02-28)

主引用文献

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

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: 23794260
DOI: 10.1002/cmdc.201300166

実験手法

X-RAY DIFFRACTION (1.91 Å)