A novel benzimidazole analogue inhibits the hypoxia-inducible factor (HIF)-1 pathway.
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-1alpha 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-1alpha through the Hsp90-Akt pathway, leading to the degradation of HIF-1alpha. 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-1alpha via the Hsp90-Akt pathway, and that it can be used as a new lead in developing anticancer drugs.
Medical Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, South Korea.
Mi-Sun
MS
Won
Namhui
N
Im
Soohyun
S
Park
Shanthaveerappa K
SK
Boovanahalli
Yinglan
Y
Jin
Xuejun
X
Jin
Kyung-Sook
KS
Chung
Moorim
M
Kang
Kiho
K
Lee
Song-Kyu
SK
Park
Hwan Mook
HM
Kim
Byoung Mog
BM
Kwon
Jung Joon
JJ
Lee
Kyeong
K
Lee
D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
C541419:AC1 004; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051057:Proto-Oncogene Proteins c-akt; D000218:Adamantane