A novel benzimidazole analogue inhibits the hypoxia-inducible factor (HIF)-1 pathway

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A novel benzimidazole analogue inhibits the hypoxia-inducible factor (HIF)-1 pathway
Mi Sun Won; N Im; S Park; S K Boovanahalli; Y Jin; X Jin; Kyung Sook Chung; Kang Moo rim; Kiho Lee; Song Kyu Park; Hwan Mook Kim; Byoung-Mog Kwon; Jung Joon Lee; Kyeong Lee
Bibliographic Citation
Biochemical and Biophysical Research Communications, vol. 385, no. 1, pp. 16-21
Publication Year
Hypoxia-inducible factor (HIF)-1 is a therapeutic target in solid tumors. We report the novel benzimidazole analogue AC1-004, obtained from a chemical library using an HRE-dependent cell-based assay in colorectal carcinoma HCT-116 cells. The accumulation of hypoxia-induced HIF-1α was inhibited by compound AC1-004 in various cancer cells, including HCT-116, MDA-MB435, SK-HEP1, and Caki-1. Further, AC1-004 down-regulated VEGF and EPO, target genes of HIF-1, and inhibited in vitro tube formation of HUVEC, suggesting its potential inhibitory activity on angiogenesis. Importantly, AC1-004 was found to regulate the stability of HIF-1α through the Hsp90-Akt pathway, leading to the degradation of HIF-1α. An in vivo antitumor study demonstrated that AC1-004 reduced tumor size significantly (i.e., by 58.6%), without severe side effects. These results suggest the benzimidazole analogue AC1-004 is a novel HIF inhibitor that targets HIF-1α via the Hsp90-Akt pathway, and that it can be used as a new lead in developing anticancer drugs.
AktangiogenesisbenzimidazoleHIF-1α inhibitorHsp90hypoxia
Appears in Collections:
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
Division of Research on National Challenges > 1. Journal Articles
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