title: A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases.
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.
authors.affiliation: Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Jupiter, Florida 33458, United States. yfeng@scripps.edu
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Chambers
authors.forename: Sarah
authors.initials: S
authors.lastname: Iqbal
authors.forename: Marcel
authors.initials: M
authors.lastname: Koenig
authors.forename: HaJeung
authors.initials: H
authors.lastname: Park
authors.forename: Lisa
authors.initials: L
authors.lastname: Cherry
authors.forename: Pamela
authors.initials: P
authors.lastname: Hernandez
authors.forename: Mariana
authors.initials: M
authors.lastname: Figuera-Losada
authors.forename: Philip V
authors.initials: PV
authors.lastname: LoGrasso
mesh_terms: D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015335:Molecular Probes / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D007191:Indazoles; D015335:Molecular Probes; C587064:SR9444; D054852:Small Molecule Libraries; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4