BIDENTATE-BINDING MODULATORS OF LRRK2 AND JNK KINASES

摘要

Both JNK and LRRK2 are associated with Parkinson's 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.

主权项

1. A bidentate kinase inhibitor compound of formula (I) wherein
each of ring C and ring C′ independently comprises 0, 1, 2, or 3 nitrogen atoms therein; or ring C′ is absent, and a direct bond or an ethynyl group bonds ring system C to group B;group A is a 3-16 membered saturated, partially unsaturated, or aromatic, mono-, bi-, or tricyclic ring system, comprising 0-8 heteroatoms selected from the group consisting of O, N, and S(O)q wherein q=0, 1, or 2, substituted with n3 R3 groups;R1, R2, and R3 are each independently at each occurrence OR, NR2, CN, CF3, halo, or a (C1-6)alkyl optionally comprising therein any of NR′, S(O)q, O, C(═S), C(═O), C(═O)O, OC(═O)O, C(═O)C(═O), C(═O)NR′, O(C═O)NR′ NR′C(═O)NR′, SO2NR′, or C(═O)NR′NR′; or R1, R2, and R3 are each independently a 3-16 membered saturated, partially unsaturated, or aromatic, mono-, bi-, or tricyclic ring system, comprising 0-8 heteroatoms selected from the group consisting of O, N, and S(O)q wherein q=0, 1, or 2, substituted with n4 R4 groups;R4 is independently at each occurrence OR, NR2, CN, CF3, halo, or a (C1-6)alkyl optionally comprising therewithin any of NR′, S(O)q, O, C(═S), C(═O), C(═O)O, OC(═O)O, C(═O)C(═O), C(═O)NR′, O(C═O)NR′ NR′C(═O)NR′, SO2NR′, or C(═O)NR′NR′;n1=0, 1, 2, or 3; n2=0, 1, 2, or 3; n3=0, 1, 2, 3, 4, or 5; n4=0, 1, 2, 3, 4, or 5;R is H, (C1-6)alkyl, or (C1-6)acyl;R′ is H, (C1-6)alkyl, or (C1-6)acyl; or R′ is a 5-16 membered saturated, partially unsaturated, or aromatic, mono-, bi-, or tricyclic ring system, comprising 0-8 heteroatoms selected from the group consisting of O, N, and S(O)q wherein q=0, 1, or 2, substituted with n4 R4 groups;B is a linker comprising at least 8 backbone atoms selected from C, N, O, and S(O)q, wherein the linker can be linear or can comprise 1-4 cycloalkyl, heterocyclyl, aryl, or heteroaryl ring systems, any of which is optionally mono- or independently multi-substituted with R′;or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, or prodrug thereof.