4I5P

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

Summary for 4I5P

• Entry DOI: 10.2210/pdb4i5p/pdb
• Descriptor: Serine/threonine-protein kinase PLK2, (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-(1H-pyrrol-2-yl)-7,8-dihydropteridin-6(5H)-one (3 entities in total)
• Functional Keywords: polo-like kinase-2 (plk-2), synuclein, 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: 36157.60

Authors

Aubele, D.L.,Hom, R.K.,Adler, M.,Galemmo Jr., R.A.,Bowers, S.,Truong, A.P.,Pan, H.,Beroza, P. (deposition date: 2012-11-28, release date: 2013-12-25, Last modification date: 2024-02-28)

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 and 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

Experimental method

X-RAY DIFFRACTION (1.738 Å)