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

ACS Chem Biol. 2013 Aug 16;8(8):1747-54. doi: 10.1021/cb3006165. Epub 2013 Jun 10.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Benzofurans / chemistry*
  • Benzofurans / pharmacology
  • Binding Sites
  • Cell Line
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Indazoles / chemistry*
  • Indazoles / pharmacology
  • Inhibitory Concentration 50
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • MAP Kinase Kinase 4 / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Probes* / chemistry
  • Molecular Probes* / pharmacology
  • Protein Binding / drug effects
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology

Substances

  • Benzofurans
  • Enzyme Inhibitors
  • Indazoles
  • Molecular Probes
  • SR9444
  • Small Molecule Libraries
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase 4