Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Aubele, Danielle L.; Hom, Roy K.; Adler, Marc; Galemmo, Robert A.; Bowers, Simeon; Truong, Anh P.; Pan, Hongyu; Beroza, Paul; Neitz, R. Jeffrey; Yao, Nanhua; Lin, Millicent; Tonn, George; Zhang, Heather; Bova, Michael P.; Zhao, Rongjun; Tam, Danny; Ruslim, Lany; Baker, Jeanne; Diep, Linnea; Fitzgerald, Kent; Hoffman, Joseph G.; Motter, Ruth; Fauss, Donald; Tanaka, Pearl; Dappen, Michael S.; Jagodziński, Jacek; Chan, Wayman; Konradi, Andrei W.; Latimer, Lee H.; Zhu, Yong; Sham, Hing L.; Anderson, John P.; Bergeron, Marcelle; Artis, Dean R.

doi:10.1002/cmdc.201300166

Cited by 45 publications

(53 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, these findings put a new complexion on experimental pharmaceutical interventions directed against POLO-2 kinase, which mediates asyn phosphorylation at Ser129 [44]. Given the potential neuroprotective effect of Ser129 phosphorylation, such interventions may not achieve relevant therapeutic effects.…”

Section: Discussionmentioning

confidence: 99%

Modelling Ser129 Phosphorylation Inhibits Membrane Binding of Pore-Forming Alpha-Synuclein Oligomers

et al. 2014

View full text Add to dashboard Cite

BackgroundIn several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn), implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding.MethodsWe investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV) composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level.ResultsBinding of asyn129E monomers to gel-state membranes (DPPC-SUV) is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV) are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe3+ induced asyn129E oligomers and markedly reduced in Al3+ induced oligomers.ConclusionThe protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase.

show abstract

Section: Discussionmentioning

confidence: 99%

Modelling Ser129 Phosphorylation Inhibits Membrane Binding of Pore-Forming Alpha-Synuclein Oligomers

et al. 2014

View full text Add to dashboard Cite

show abstract

“…(A) The Plk1 catalytic domain with BI 2536 (brown; PDB 2RKU) [53] and volasertib (green; PDB 3FC2) [94]; (B) the Plk2 catalytic domain with 1C8 (PDB 4I6H), [152]; and (C) the Plk3 catalytic domain with 9ZP (PDB 4B6L) are shown. (Left) The active sites of Plks are displayed in stick models in the left panel.…”

Section: Figurementioning

confidence: 99%

Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

Lee

Burke

Park

et al. 2015

Trends in Pharmacological Sciences

107

134

View full text Add to dashboard Cite

Polo-like kinase 1 (Plk1) plays key roles in regulating mitotic processes that are critical for cellular proliferation. Overexpression of Plk1 is tightly associated with the development of certain cancers in humans, and a large body of evidence suggests that Plk1 is an attractive target for anticancer therapeutic development. Drugs targeting Plk1 can potentially be directed at two distinct sites: the N-terminal catalytic domain, which phosphorylates substrates, and the C-terminal polo-box domain, which is essential for protein–protein interactions. In this review, we will summarize recent advances and new challenges in the development of Plk1 inhibitors targeting these two domains. We will also discuss novel strategies for designing and developing next-generation inhibitors to effectively treat Plk1-associated human disorders.

show abstract

“…Compared to Plk2 and Plk3, residues that are specific (green) or semi-specific (red) to Plk1 are labeled. Notably, the aryl-methoxy group in region II (near L132 of the hinge region) is used to produce moderate selectivity for Plk1 against other Plks 44 .…”

Section: Future Strategies To Conquer Current Obstaclesmentioning

confidence: 99%

“…This difference has been exploited to generate inhibitors that demonstrate ~1,000-fold selectivity for Plk2 versus Plk1 44 . Such work highlights what can be achieved using structure-based drug design to take advantage of small differences in protein-binding sites.…”

Section: Future Strategies To Conquer Current Obstaclesmentioning

confidence: 99%

Current progress and future perspectives in the development of anti-polo-like kinase 1 therapeutic agents

et al. 2017

View full text Add to dashboard Cite

Although significant levels of side effects are often associated with their use, microtubule-directed agents that primarily target fast-growing mitotic cells have been considered to be some of the most effective anti-cancer therapeutics. With the hope of developing new-generation anti-mitotic agents with reduced side effects and enhanced tumor specificity, researchers have targeted various proteins whose functions are critically required for mitotic progression. As one of the highly attractive mitotic targets, polo-like kinase 1 (Plk1) has been the subject of an extensive effort for anti-cancer drug discovery. To date, a variety of anti-Plk1 agents have been developed, and several of them are presently in clinical trials. Here, we will discuss the current status of generating anti-Plk1 agents as well as future strategies for designing and developing more efficacious anti-Plk1 therapeutics.

show abstract

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Cited by 45 publications

References 56 publications

Modelling Ser129 Phosphorylation Inhibits Membrane Binding of Pore-Forming Alpha-Synuclein Oligomers

Modelling Ser129 Phosphorylation Inhibits Membrane Binding of Pore-Forming Alpha-Synuclein Oligomers

Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

Current progress and future perspectives in the development of anti-polo-like kinase 1 therapeutic agents

Contact Info

Product

Resources

About