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 Citations (Scopus)

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
Externally publishedYes

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MAP Kinase Kinase 4
Phosphotransferases
Molecules
Parkinson Disease
Adenosine Triphosphate
Enzyme Inhibitors
Hinges
Inhibitory Concentration 50
Membrane Proteins
Testing
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Feng, Y., Chambers, J. W., Iqbal, S., Koenig, M., Park, H., Cherry, L., ... 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

A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases. / Feng, Yangbo; Chambers, Jeremy W.; Iqbal, Sarah; Koenig, Marcel; Park, Hajeung; Cherry, Lisa; Hernandez, Pamela; Figuera-Losada, Mariana; Lograsso, Philip V.

In: ACS Chemical Biology, Vol. 8, No. 8, 16.08.2013, p. 1747-1754.

Research output: Contribution to journalArticle

Feng, Y, Chambers, JW, Iqbal, S, Koenig, M, Park, H, Cherry, L, Hernandez, P, Figuera-Losada, M & Lograsso, PV 2013, 'A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases', ACS Chemical Biology, vol. 8, no. 8, pp. 1747-1754. https://doi.org/10.1021/cb3006165
Feng Y, Chambers JW, Iqbal S, Koenig M, Park H, Cherry L et al. A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases. ACS Chemical Biology. 2013 Aug 16;8(8):1747-1754. https://doi.org/10.1021/cb3006165
Feng, Yangbo ; Chambers, Jeremy W. ; Iqbal, Sarah ; Koenig, Marcel ; Park, Hajeung ; Cherry, Lisa ; Hernandez, Pamela ; Figuera-Losada, Mariana ; Lograsso, Philip V. / A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases. In: ACS Chemical Biology. 2013 ; Vol. 8, No. 8. pp. 1747-1754.
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