Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors

Tumor hypoxia has been recognized as a common feature of solid tumors and a negative prognostic factor for response to treatment and survival of cancer patients. The discovery of hypoxia-inducible factor-1 (HIF-1), a molecular determinant of responses to hypoxia in mammalian cells, has renewed enthusiasm for discovery and development of targeted therapies exploiting the hypoxic tumor microenvironment. HIF-1 activity in tumors depends on availability of the HIF-1α subunit, the levels of which increase under hypoxic conditions and through activation of oncogenes and/or inactivation of tumor suppressor genes. Increased HIF-1 has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to current interest in HIF-1 as promising anticancer drug target. In spite of an ever increasing number of putative small molecule inhibitors of HIF-1, only a few are progressing through preclinical and early clinical development. In this review, we will discuss recent advances in discovery and development of small molecule inhibitors that target the HIF-1 pathway as potential anticancer agents. In the first part the review describes the structure of HIF, regulation of HIF-1α protein levels and the target genes of HIF-1. The main part of this review is related to recent development of small molecule HIF-1 inhibitors that affect the HIF-1 through many pathways as shown in the figure. [Display omitted] ► Inhibitor of HIF-1 pathway is an important class of therapeutic agents with far-reaching implications in oncology and related area. ► We review recent advances on small molecule inhibitors of HIF-1 function. ► We give an overview of these agents in terms of their biological modes on this pathway. ► We outlook HIF-1 inhibitors as drug candidates for potential anticancer drug.