Development of novel inhibitors targeting HIF-1α towards anticancer drug discovery

Hypoxia-inducible factor-1α (HIF-1α) is a critical regulatory protein of cellular response to hypoxia, and regulates the transcription of many genes involved in key aspects of cancer biology, including immortalization, maintenance of stem cell pools, cellular dedifferentiation, vascularization, and invasion/metastasis. HIF-1α has been implicated in the regulation of genes involved in angiogenesis, for example, VEGF and is associated with tumor progression. In the last decade, over expression of HIF-1α has been demonstrated in many common human cancers and emerging as a validated target for anticancer drug discovery. Here we report the discovery of newly designed and synthesized pyridylpyrimidine based potent and selective inhibitors of HIF-1α. P2630 has been found as potent antiproliferative, antiangiogenic and orally efficacious compound in PC-3 xenograft mice model.

Graphical abstractSystemic application of compound P2630, a novel HIF-1α inhibitor, significantly suppresses the cell proliferation angiogenesis. P2630 has been shown orally efficacious in PC-3 xenograft mice model.Figure optionsDownload full-size imageDownload as PowerPoint slide