Hypoxia-inducible factor (HIF) is a central regulator involved in detection and adaption to cellular oxygen stress through regulation of the hypoxic transcriptional program in angiogenesis, erythropoiesis, and metabolism. The HIF pathway is involved in many diseases. On one hand, overexpression of the HIF pathway is associated with solid tumors such as renal cell carcinoma (RCC). On the other hand, suppression of the HIF pathway is correlated with inflammatory, anemia, and other hypoxic–ischemic diseases. Therefore, modulation of the HIF pathway has been perceived as a promising strategy for treating HIF-related diseases. Recent advances in understanding of the biochemistry underlying the HIF pathway have stimulated small-molecule drugs development, and therapeutically, manipulation of the HIF-mediated response has been shown to have considerable medicinal potential. This review will summarize and provide insight into recent advances in research that have expanded our knowledge of the HIF pathway, including its structural basis and biology, small-molecule modulators of the pathway, including inhibitors and activators, and the potential therapeutic applications of these modulators.

Factor inhibiting hypoxia-inducible factor (FIH) is a JmjC domain 2-oxogluarate and Fe(II)-dependent oxygenase that catalyzes hydroxylation of specific asparagines in the Cterminal transcriptional activation domain of hypoxia-inducible factor alpha (HIF-α) isoforms. This modification suppresses the transcriptional activity of HIF by reducing its interaction with the transcriptional coactivators p300/CBP. By contrast with inhibition of the HIF prolyl hydroxylases (PHDs), inhibitors of FIH, which accepts multiple non-HIF substrates, are less studied; they are of interest due to their potential ability to alter metabolism (either in a HIF-dependent and/or -independent manner) and, provided HIF is upregulated, to modulate the course of the HIF-mediated hypoxic response. Here we review studies on the mechanism and inhibition of FIH. We discuss proposed biological roles of FIH including its regulation of HIF activity and potential roles of FIHcatalyzed oxidation of non-HIF substrates. We highlight potential therapeutic applications of FIH inhibitors.

HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor (7) of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene. Light activation to stabilize HIF offers promising potentials for the tissue-specific therapies for HIF-related disease by light irradiation onto target tissues.

Page 7585. In line 8 of the left column, "UV−vis spectroscopy" should be "emission spectroscopy".Page 7585. In the Figure 4A legend, "Absorption" should be "Emission".Page 7585. In the Figure 4B legend, "UV−vis spectra" should be "emission spectra".Page 7585. In line 12 of the left column, "absorption" should be "emission".Page 7585. In lines 1, 2, 3, 4, and 6 of the right column, "absorption" should be "emission".Page 7587. In lines 52 and 56 of the left column (i.e., lines 9 and 13 of the section "Visible-Light-Excitation-Induced Photorelease Assay"), "absorption" should be "emission".