التفاصيل البيبلوغرافية
| العنوان: |
Aurone derivatives as Vps34 inhibitors that modulate autophagy. |
| المؤلفون: |
Li, Guodong, Boyle, Joshua William, Ko, Chung-Nga, Zeng, Wu, Wong, Vincent Kam Wai, Wan, Jian-Bo, Chan, Philip Wai Hong, Ma, Dik-Lung, Leung, Chung-Hang |
| المصدر: |
Acta Pharmaceutica Sinica B; May2019, Vol. 9 Issue 3, p537-544, 8p |
| مصطلحات موضوعية: |
MTOR inhibitors, THERAPEUTICS, STARVATION, MORPHOLOGY, LIVER |
| مستخلص: |
We report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases. We identified aurone derivative 1a as an ATP-competitive inhibitor of Vps34 inhibitor. 1a prevented autophagy in human cells induced either by starvation or by an mTOR inhibitor. In vivo examination showed that 1a was able to promote p62 accumulation without affecting the morphology of mice heart and liver. fx1 [ABSTRACT FROM AUTHOR] |
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