An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors.,Journal of Medicinal Chemistry

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An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-16 , DOI: 10.1021/acs.jmedchem.9b01685
Wen Zhang , Vitaliy M Sviripa , Liliia M Kril , Tianxin Yu , Yanqi Xie , W Brad Hubbard , Patrick G Sullivan , Xi Chen , Chang-Guo Zhan , Yang Yang-Hartwich ₁ , B Mark Evers , Brett T Spear , Roberto Gedaly , David S Watt , Chunming Liu

Affiliation

The importance of upregulated Wnt signaling in colorectal cancers led to efforts to develop inhibitors that target β-catenin in this pathway. We now report that several "Wnt inhibitors" that allegedly target β-catenin actually function as mitochondrial proton uncouplers that independently activate AMPK and concomitantly inhibit Wnt signaling. As expected for a process in which mitochondrial uncoupling diminishes ATP production, a mitochondrial proton uncoupler, FCCP, and a glucose metabolic inhibitor, 2-DG, activated AMPK and inhibited Wnt signaling. Also consistent with these findings, a well-known "Wnt inhibitor", FH535, functioned as a proton uncoupler, and in support of this finding, the N-methylated analog, 2,5-dichloro-N-methyl-N-(2-methyl-4-nitrophenyl)benzenesulfonamide (FH535-M), was inactive as an uncoupler and Wnt inhibitor. Apart from suggesting an opportunity to develop dual Wnt inhibitors and AMPK activators, these findings provide a cautionary tale that claims for Wnt inhibition alone require scrutiny as possible mitochondrial proton uncouplers or inhibitors of the electron transport chain.

中文翻译：

Wnt 双重抑制和 AMPK 激活的潜在机制：伪装成 Wnt 抑制剂的线粒体解偶联剂。

Wnt 信号上调在结直肠癌中的重要性促使人们努力开发针对该通路中 β-catenin 的抑制剂。我们现在报道了几种据称针对 β-连环蛋白的“Wnt 抑制剂”实际上充当线粒体质子解偶联剂，独立激活 AMPK 并同时抑制 Wnt 信号传导。正如线粒体解偶联减少 ATP 产生的过程所预期的那样，线粒体质子解偶联剂 FCCP 和葡萄糖代谢抑制剂 2-DG 激活 AMPK 并抑制 Wnt 信号传导。同样与这些发现一致的是，一种著名的“Wnt 抑制剂”FH535 充当质子解偶联剂，并且支持这一发现的 N-甲基化类似物 2,5-二氯-N-甲基-N-(2 -甲基-4-硝基苯基)苯磺酰胺 (FH535-M) 作为解偶联剂和 Wnt 抑制剂没有活性。除了提出开发双重 Wnt 抑制剂和 AMPK 激活剂的机会外，这些发现还提供了一个警示，即单独抑制 Wnt 的主张需要仔细审查，因为可能是线粒体质子解偶联剂或电子传递链抑制剂。

更新日期：2019-12-17

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