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    BIDENTATE-BINDING MODULATORS OF LRRK2 AND JNK KINASES
    4.
    发明公开
    BIDENTATE-BINDING MODULATORS OF LRRK2 AND JNK KINASES 审中-公开
    LRRK2和JNK激酶的双键结合调节剂

    公开(公告)号：EP3003302A4

    公开(公告)日：2016-12-14

    申请号：EP14811712

    申请日：2014-05-22

    申请人： SCRIPPS RESEARCH INST

    发明人： FENG YANGBO ,  LOGRASSO PHILIP

    IPC分类号： C07D405/12 ,  A61K31/416 ,  C07D231/56 ,  C07D319/16

    CPC分类号： C07K5/06026 ,  A61K31/416 ,  A61K38/00 ,  C07D231/56 ,  C07D405/12 ,  C07K5/101 ,  C07K7/06

    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.

    摘要翻译： JNK和LRRK2都与帕金森病（PD），心肌梗死（MI）和其他医学疾病有关。 在这里，我们报告了结合JNK和LRRK2（双重抑制剂）的合理选择性和有效的激酶抑制剂（例如，化合物6和10）。 同时使用ATP铰链结合和ATP口袋外的独特蛋白质表面位点的二齿结合策略被应用于这种抑制剂的设计和鉴定。 化合物6是分别具有12nM和99nM（LRRK2-G2019S）的酶IC 50值的有效的JNK3和适度的LRRK2双重抑制剂。 6还表现出良好的细胞效能，抑制LRRK2：G2019S诱导SHSY5Y细胞的线粒体功能障碍，并且证明对来自代表性激酶家族的116个激酶的组合具有合理的选择性。