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Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce α-synuclein phosphorylation in rat brain.

Aubele DL, Hom RK, Adler M, Galemmo RA, 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 8 1295-313 (2013)
Related entries: 4i5m, 4i6b, 4i6f, 4i6h

Cited: 21 times
EuropePMC logo PMID: 23794260

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.

Articles - 4i5p mentioned but not cited (2)

  1. Plk2 Loss Commonly Occurs in Colorectal Carcinomas but not Adenomas: Relationship to mTOR Signaling. Matthew EM, Yang Z, Peri S, Andrake M, Dunbrack R, Ross E, El-Deiry WS. Neoplasia 20 244-255 (2018)
  2. A Major Diplotaxis harra-Derived Bioflavonoid Glycoside as a Protective Agent against Chemically Induced Neurotoxicity and Parkinson's Models; In Silico Target Prediction; and Biphasic HPTLC-Based Quantification. Ahmed AF, Wen ZH, Bakheit AH, Basudan OA, Ghabbour HA, Al-Ahmari A, Feng CW. Plants (Basel) 11 648 (2022)


Reviews citing this publication (6)

  1. Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy. Lee KS, Burke TR, Park JE, Bang JK, Lee E. Trends Pharmacol Sci 36 858-877 (2015)
  2. Targeting α-synuclein for PD Therapeutics: A Pursuit on All Fronts. Teil M, Arotcarena ML, Faggiani E, Laferriere F, Bezard E, Dehay B. Biomolecules 10 E391 (2020)
  3. Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies. Kawahata I, Finkelstein DI, Fukunaga K. Int J Mol Sci 23 6216 (2022)
  4. Current progress and future perspectives in the development of anti-polo-like kinase 1 therapeutic agents. Park JE, Hymel D, Burke TR, Lee KS. F1000Res 6 1024 (2017)
  5. Therapeutic potential of pteridine derivatives: A comprehensive review. Carmona-Martínez V, Ruiz-Alcaraz AJ, Vera M, Guirado A, Martínez-Esparza M, García-Peñarrubia P. Med Res Rev 39 461-516 (2019)
  6. Polo-Like Kinase 2: From Principle to Practice. Zhang C, Ni C, Lu H. Front Oncol 12 956225 (2022)

Articles citing this publication (13)

  1. In vivo modulation of polo-like kinases supports a key role for PLK2 in Ser129 α-synuclein phosphorylation in mouse brain. Bergeron M, Motter R, Tanaka P, Fauss D, Babcock M, Chiou SS, Nelson S, San Pablo F, Anderson JP. Neuroscience 256 72-82 (2014)
  2. Genetic deletion of Polo-like kinase 2 reduces alpha-synuclein serine-129 phosphorylation in presynaptic terminals but not Lewy bodies. Weston LJ, Stackhouse TL, Spinelli KJ, Boutros SW, Rose EP, Osterberg VR, Luk KC, Raber J, Weissman TA, Unni VK. J Biol Chem 296 100273 (2021)
  3. Small molecule annotation for the Protein Data Bank. Sen S, Young J, Berrisford JM, Chen M, Conroy MJ, Dutta S, Di Costanzo L, Gao G, Ghosh S, Hudson BP, Igarashi R, Kengaku Y, Liang Y, Peisach E, Persikova I, Mukhopadhyay A, Narayanan BC, Sahni G, Sato J, Sekharan M, Shao C, Tan L, Zhuravleva MA. Database (Oxford) 2014 bau116 (2014)
  4. Age- and brain region-dependent α-synuclein oligomerization is attributed to alterations in intrinsic enzymes regulating α-synuclein phosphorylation in aging monkey brains. Chen M, Yang W, Li X, Li X, Wang P, Yue F, Yang H, Chan P, Yu S. Oncotarget 7 8466-8480 (2016)
  5. Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. Nübling GS, Levin J, Bader B, Lorenzl S, Hillmer A, Högen T, Kamp F, Giese A. PLoS One 9 e98906 (2014)
  6. Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein. Elfarrash S, Jensen NM, Ferreira N, Schmidt SI, Gregersen E, Vestergaard MV, Nabavi S, Meyer M, Jensen PH. PLoS One 16 e0252635 (2021)
  7. PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells. Hu ZB, Liao XH, Xu ZY, Yang X, Dong C, Jin AM, Lu H. Cancer Med 5 74-87 (2016)
  8. Polo-like kinase 2 acting as a promoter in human tumor cells with an abundance of TAp73. Hu Z, Xu Z, Liao X, Yang X, Dong C, Luk K, Jin A, Lu H. Onco Targets Ther 8 3475-3488 (2015)
  9. Deficient immunoproteasome assembly drives gain of α-synuclein pathology in Parkinson's disease. Bi M, Du X, Xiao X, Dai Y, Jiao Q, Chen X, Zhang L, Jiang H. Redox Biol 47 102167 (2021)
  10. Highly Atom Economic Synthesis of d-2-Aminobutyric Acid through an In Vitro Tri-enzymatic Catalytic System. Chen X, Cui Y, Cheng X, Feng J, Wu Q, Zhu D. ChemistryOpen 6 534-540 (2017)
  11. Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2). Reddy MV, Akula B, Jatiani S, Vasquez-Del Carpio R, Billa VK, Mallireddigari MR, Cosenza SC, Venkata Subbaiah DR, Bharathi EV, Pallela VR, Ramkumar P, Jain R, Aggarwal AK, Reddy EP. Bioorg Med Chem 24 521-544 (2016)
  12. Study of trioleoylglycerol two-layer and adiposome cross-section mimicking four-layer systems through atomic-level simulations. Mirza AH. Struct Dyn 9 064701 (2022)
  13. Zinc chloride-catalyzed cyclizative 1,2-rearrangement enables facile access to morpholinones bearing aza-quaternary carbons. Li XZ, He YP, Wu H. Commun Chem 6 216 (2023)


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