Abstract
Hypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches. Here, we surveyed small-molecule compounds that efficiently inhibit the transcriptional activity of HIF-1 without affecting body homoeostasis. We focused on Mint3, which activates HIF-1 transcriptional activity in limited types of cells, such as cancer cells and macrophages, by suppressing the factor inhibiting HIF-1 (FIH-1). We identified naphthofluorescein, which inhibited the Mint3–FIH-1 interaction in vitro and suppressed Mint3-dependent HIF-1 activity and glycolysis in cancer cells and macrophages without evidence of cytotoxicity in vitro. In vivo naphthofluorescein administration suppressed tumour growth and metastasis without adverse effects, similar to the genetic depletion of Mint3. Naphthofluorescein attenuated inflammatory cytokine production and endotoxic shock in mice. Thus, Mint3 inhibitors may present a new targeted therapeutic option for cancer and inflammatory diseases by avoiding severe adverse effects.
Highlights
Hypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches
Mint[3] depletion suppresses tumour growth of various types of cancer, such as breast cancer, pancreatic cancer, lung cancer, and fibrosarcoma, and enhances chemosensitivity in cancer cells[18,20,21,28]. These results indicate that Mint[3] inhibitors may present a new targeted therapeutic option for cancer and inflammatory diseases by avoiding severe adverse effects
To further explore potent Mint[3] inhibitors, 18 compounds that were structurally similar to compound #1 were collected and subjected to the HIF-1 reporter assay in HT1080 cells (Supplementary Table 1)
Summary
Hypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches. HIF-1 is essential for cancer and inflammatory diseases and for body homoeostasis; HIF-1α knockout in mice is embryonically lethal at day E11 due to cardiovascular malfunctions and neural tube defects, whereas HIF-1α conditional knockout mice show various defects in this regard[7,8,9,10,11,12]. Mint[3] is expressed ubiquitously, whereas
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