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A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases

Academic Article
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Overview

authors

  • Feng, Yangbo
  • Chambers, J. W.
  • Iqbal, S.
  • Koenig, M.
  • Park, HaJeung
  • Cherry, L.
  • Hernandez, P.
  • Figuera-Losada, M.
  • LoGrasso, Philip

publication date

  • August 2013

journal

  • ACS Chemical Biology  Journal

abstract

  • Both JNK and LRRK2 are associated with Parkinson's disease (PD). Here we report a reasonably selective and potent kinase inhibitor (compound 6) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. Compound 6 also exhibited good cell potency, inhibited LRRK2:G2019S-induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families. Design of such a probe molecule may help enable testing if dual JNK and LRRK2 inhibitions have added or synergistic efficacy in protecting against neurodegeneration in PD.

subject areas

  • Benzofurans
  • Binding Sites
  • Cell Line
  • Enzyme Activation
  • Enzyme Inhibitors
  • Humans
  • Indazoles
  • Inhibitory Concentration 50
  • MAP Kinase Kinase 4
  • Models, Molecular
  • Molecular Probes
  • Protein Binding
  • Protein Serine-Threonine Kinases
  • Small Molecule Libraries
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Identity

PubMed Central ID

  • PMC3759981

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb3006165

PubMed ID

  • 23751758
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Additional Document Info

start page

  • 1747

end page

  • 1754

volume

  • 8

issue

  • 8

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