A Small Molecule Bidentate-Binding Dual Inhibitor Probe of the LRRK2 and JNK Kinases

作者：Feng Yangbo^*; Chambers Jeremy W; Iqbal Sarah; Koenig Marcel; Park HaJeung; Cherry Lisa; Hernandez Pamela; Figuera Losada Mariana; LoGrasso Philip V

来源：ACS Chemical Biology, 2013, 8(8): 1747-1754.

DOI：10.1021/cb3006165

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.

• 出版日期2013-8