Identification and characterization of small molecules as potent and specific EPAC2 antagonists.
Identification and characterization of small molecules as potent and specific EPAC2 antagonists.
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DOI：
10.1021/jm3014162
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发表时间：
2013-02-14
影响因子：
7.3
通讯作者：
Zhou, Jia
中科院分区：
文献类型：
--
作者：
Chen, Haijun;Tsalkova, Tamara;Chepurny, Oleg G.;Mei, Fang C.;Holz, George G.;Cheng, Xiaodong;Zhou, Jia
EPAC1和Epac2是两种由cAMP直接激活的交换蛋白，它们响应第二信使cAMP，在生理和病理生理条件下调节多种细胞内过程。在这里，我们报道了三种不同的支架(二芳基砜、N，N-二芳胺和芳基磺酰胺)作为Epac2的高效和选择性拮抗剂的化学设计、合成和药理学表征。一些选择性的Epac2拮抗剂已经被发现，包括20i(HJC0350)，它与Epac2的8-NBD-cAMP结合的明显IC50值为0.3微米，其效力约为cAMP的133倍。化合物1(ESI-05)、14c(HJC0338)和20i在25µM没有表现出对EPAC1介导的Rap1-GDP交换活性的抑制，表明它们是Epac2特异性拮抗剂。此外，使用EPAC1、Epac2或PKA FRET传感器的活细胞成像研究也表明20i作为Epac2的特异性拮抗剂发挥作用。
EPAC1 and EPAC2, two isoforms of exchange proteins directly activated by cAMP (EPAC), respond to the second messenger cAMP and regulate a wide variety of intracellular processes under physiological and pathophysiological circumstances. Herein, we report the chemical design, synthesis, and pharmacological characterization of three different scaffolds (diaryl sulfones, N,N-diarylamines, and arylsulfonamides) as highly potent and selective antagonists of EPAC2. Several selective EPAC2 antagonists have been identified including 20i (HJC0350), which has an apparent IC50 value of 0.3 µM for competing with 8-NBD-cAMP binding of EPAC2, and is about 133-fold more potent than cAMP. Compounds 1(ESI-05), 14c (HJC0338) and 20i, selected from each series, have exhibited no inhibition of EPAC1-mediated Rap1-GDP exchange activity at 25 µM, indicating that they are EPAC2-specific antagonists. Moreover, live-cell imaging studies using EPAC1, EPAC2, or PKA FRET sensor also demonstrate that 20i functions as an EPAC2 specific antagonist
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影响因子：
11.2
作者：
Lissitzky, Jean-Claude;Parriaux, Danielle;Verrando, Patrick
通讯作者：
Verrando, Patrick
影响因子：
56.9
作者：
Kawasaki, H;Springett, GM;Graybiel, AM
通讯作者：
Graybiel, AM
影响因子：
2.7
作者：
Chen, Haijun;Tsalkova, Tamara;Mei, Fang C.;Hu, Yaohua;Cheng, Xiaodong;Zhou, Jia
通讯作者：
Zhou, Jia
影响因子：
4.8
作者：
Li, Sheng;Tsalkova, Tamara;Cheng, Xiaodong
通讯作者：
Cheng, Xiaodong
影响因子：
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作者：
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通讯作者：
Zhang, Jin