A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases.
A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases.
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DOI：
10.1021/cb3006165
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发表时间：
2013-08-16
影响因子：
4
通讯作者：
LoGrasso, Philip V.
中科院分区：
文献类型：
--
作者：
Feng, Yangbo;Chambers, Jeremy W.;Iqbal, Sarah;Koenig, Marcel;Park, HaJeung;Cherry, Lisa;Hernandez, Pamela;Figuera-Losada, Mariana;LoGrasso, Philip V.
JNK和LRRK 2都与帕金森病（PD）有关。在这里，我们报告了一个合理的选择性和有效的激酶抑制剂（化合物6），结合JNK和LRRK 2（双重抑制剂）。一个双齿结合的策略，同时利用ATP铰链结合和一个独特的蛋白质表面位点外的ATP口袋被应用到这种抑制剂的设计和鉴定。化合物6是一种有效的JNK 3和适度的LRRK 2双重抑制剂，其酶IC 50值分别为12 nM和99 nM（LRRK 2-G2019 S）。6还表现出良好的细胞效力，抑制LRRK 2：G2019 S诱导的SHSY 5 Y细胞中的线粒体功能障碍，并且被证明对来自代表性激酶家族的一组116种激酶具有合理的选择性。这种探针分子的设计可能有助于测试双重JNK和LRRK 2抑制是否在保护PD中的神经变性方面具有附加或协同功效。
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. 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.
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影响因子：
2.7
作者：
Bowers, Simeon;Truong, Anh P.;Griswold-Prenner, Irene
通讯作者：
Griswold-Prenner, Irene
影响因子：
4.8
作者：
Ho, DT;Bardwell, AJ;Bardwell, L
通讯作者：
Bardwell, L
影响因子：
4
作者：
Chambers, Jeremy W.;Cherry, Lisa;Laughlin, John D.;Figuera-Losada, Mariana;LoGrasso, Philip V.
通讯作者：
LoGrasso, Philip V.
影响因子：
4.8
作者：
Chambers, Jeremy W.;LoGrasso, Philip V.
通讯作者：
LoGrasso, Philip V.
影响因子：
4.8
作者：
Barr, RK;Boehm, I;Bogoyevitch, MA
通讯作者：
Bogoyevitch, MA