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

Yangbo Feng, Jeremy W. Chambers, Sarah Iqbal, Marcel Koenig, Hajeung Park, Lisa Cherry, Pamela Hernandez, Mariana Figuera-Losada, Philip V. Lograsso

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1747-1754
Number of pages8
JournalACS Chemical Biology
Volume8
Issue number8
DOIs
StatePublished - Aug 16 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Feng, Y., Chambers, J. W., Iqbal, S., Koenig, M., Park, H., Cherry, L., Hernandez, P., Figuera-Losada, M., & Lograsso, P. V. (2013). A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases. ACS Chemical Biology, 8(8), 1747-1754. https://doi.org/10.1021/cb3006165