A Small Molecule Bidentate-Binding Dual Inhibitor Probe of the LRRK2 and JNK Kinases
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- 作者：Yangbo Feng ; Jeremy W. Chambers ; Sarah Iqbal ; Marcel Koenig ; HaJeung Park ; Lisa Cherry ; Pamela Hernandez ; Mariana Figuera-Losada ; Philip V. LoGrasso
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：August 16, 2013
- 年：2013
- 卷：8
- 期：8
- 页码：1747-1754
- 全文大小：414K
- 年卷期：v.8,no.8(August 16, 2013)
- ISSN：1554-8937
文摘
Both JNK and LRRK2 are associated with Parkinson鈥檚 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.