Both JNK and LRRK2 are associated with Parkinsons disease (PD), myocardial infarction (MI), and other medical disorders. Here we report a reasonably selective and potent kinase inhibitors (e.g., compounds 6 and 10) 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. 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.
