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

作者：Won Mi Sun; Im Namhui; Park Soohyun; Boovanahalli Shanthaveerappa K; Jin Yinglan; Jin Xuejun; Chung Kyung Sook; Kang Moorim; Lee Kiho; Park Song Kyu; Kim Hwan Mook; Kwon Byoung Mog; Lee Jung Joon^*; Lee Kyeong

来源：Biochemical and Biophysical Research Communications, 2009, 385(1): 16-21.

DOI：10.1016/j.bbrc.2009.05.022

• Hypoxia
• HlF-1 alpha inhibitor
• Benzimidazole
• Angiogenesis
• Hsp90
• Akt

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-1 alpha 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-1 alpha through the Hsp90-Akt pathway, leading to the degradation of HIF-1 alpha. 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-1 alpha via the Hsp90-Akt pathway, and that it can be used as a new lead in developing anticancer drugs.

• 出版日期2009-7-17