2. Academic Validation
  3. Synthesis and evaluation of the HIF-1α inhibitory activity of 3(5)-substituted-4-(quinolin-4-yl)- and 4-(2-phenylpyridin-4-yl)pyrazoles as inhibitors of ALK5

Synthesis and evaluation of the HIF-1α inhibitory activity of 3(5)-substituted-4-(quinolin-4-yl)- and 4-(2-phenylpyridin-4-yl)pyrazoles as inhibitors of ALK5

  • Bioorg Med Chem Lett. 2020 Jan 15;30(2):126822. doi: 10.1016/j.bmcl.2019.126822.
Yan-Wei Li 1,  Xiang-Yu Li 2,  Shanji Li 3,  Li-Min Zhao 2,  Juan Ma 2,  Hu-Ri Piao 2,  Zhe Jiang 4,  Cheng Hua Jin 5,  Xuejun Jin 6
Affiliations

Affiliations

  • 1 Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, PR China; Pharmacy Intravenous Admixture Services, Yanbian University Hospital, Yanji 133000, PR China.
  • 2 Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, PR China.
  • 3 The School of Public Health, Jilin Medical University, Jilin 132013, PR China.
  • 4 Pharmacy Intravenous Admixture Services, Yanbian University Hospital, Yanji 133000, PR China. Electronic address: [email protected].
  • 5 Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, PR China. Electronic address: [email protected].
  • 6 Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, PR China. Electronic address: [email protected].
PMID: 31810777 DOI: 10.1016/j.bmcl.2019.126822
Abstract

The transcription factor hypoxia-inducible factor-1α (HIF-1α) 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-1α inhibitory activity at the enzyme and cell levels. The effect of the lead compound 20d (J-1012) on HIF-1α activation in HCT116 cells was investigated. J-1012 markedly decreased the hypoxia-induced or TNF-induced accumulation of HIF-1α protein dose-dependently. Analysis revealed that J-1012 inhibited HIF-1α protein synthesis, without affecting the degradation of HIF-1α protein. Furthermore, by inhibiting the activation of HIF-1α, 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.

Keywords

ALK5 inhibitor; Apoptosis; Docking; HIF-1α; TGF-β.

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