期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 30, 期 2, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.126822
关键词
TGF-beta; ALK5 inhibitor; HIF-1 alpha; Apoptosis; Docking
资金
- National Science Foundation of China [81560557, 81760657, 81660608]
- Education Department of Jilin Province Scientific Research Fund Project [2016-283]
- Jilin Province Science and Technology Development Outstanding Young Talents [20180520057JH]
- Yanbian University [31]
- 13th five-year program of science and technology of the Ministry of Education of Jilin Province [JJKH20191152KJ]
The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in apoptosis, metastasis, and proliferation and is recognized as an important potential therapeutic target for cancer. Six series of 3(5)-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)pyrazoles (11a-d, 12a-d, and 18a-d) and 3(5)-(6-methylpyridin-2-yl)-4-(2-phenyl-pyridin-4-yl)pyrazoles (19a-d, 20a-d, and 21a-d) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) and HIF-1 alpha inhibitory activity at the enzyme and cell levels. The effect of the lead compound 20d (J-1012) on HIF-1 alpha activation in HCT116 cells was investigated. J-1012 markedly decreased the hypoxia-induced or TNF-induced accumulation of HIF-1 alpha protein dose-dependently. Analysis revealed that J-1012 inhibited HIF-1 alpha protein synthesis, without affecting the degradation of HIF-1 alpha protein. Furthermore, by inhibiting the activation of HIF-1 alpha, J-1012 suppressed the metastasis and proliferation and promoted apoptosis of HCT116 cells. These results suggest that J-1012 may be a potential therapeutic agent against human colon cancer.
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