4i6b
From Proteopedia
Selective & Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors that Reduce -Synuclein Phosphorylation in Rat Brain
Structural highlights
Function[PLK2_HUMAN] Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress.[1] [2] [3] [4] Publication Abstract from PubMedPolo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of alpha-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 alpha-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. Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce alpha-Synuclein Phosphorylation in Rat Brain.,Aubele DL, Hom RK, Adler M, Galemmo RA Jr, Bowers S, Truong AP, Pan H, Beroza P, Neitz RJ, Yao N, Lin M, Tonn G, Zhang H, Bova MP, 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 AW, Latimer L, Zhu YL, Sham HL, Anderson JP, Bergeron M, Artis DR ChemMedChem. 2013 Aug;8(8):1295-313. doi: 10.1002/cmdc.201300166. Epub 2013 Jun, 21. PMID:23794260[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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