Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015)

ABSTRACT

Introduction: Hypoxia-inducible factor (HIF)-1α regulates the expression of genes involved in angiogenesis, cellular energy metabolism, and cell survival during cancer development. The increased expression of HIF-1α in most solid tumors is associated with poor prognoses and therapeutic outcomes. Therefore, HIF has been recognized as an attractive target for cancer therapy, and many HIF inhibitors have been reported.

Areas covered: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years (2011–2015).

Expert opinion: Although many of the HIF inhibitors reviewed in this patent survey possess inhibitory activity against cancer and HIF-related diseases, the compounds are still in the early stages of development, most likely due to the complexity of the HIF-1 pathway and their different mechanisms of action for HIF inhibition. Most cancer cells use the glycolytic pathway for energy production and HIF-1α participates deeply in the expression of several glycolytic enzymes. Therefore, a detailed study of HIF’s function in cancer metabolisms may provide us an alternative strategy for further development of HIF inhibitors in cancer therapy.

KEYWORDS:

• Carcinogenesis
• cancer
• hypoxia
• hypoxia-inducible factor (HIF)
• HIF inhibitors

Article highlights

• HIF is a pro-oncogenic transcription factor that regulates tumor growth, angiogenesis and metastasis under low oxygen tension.

• Various types of HIF regulators having different mechanisms of action for HIF inhibition have been developed.

• Indirect HIF regulators reduce the level of HIF-1α protein through regulation of HIF-1α translation or stabilization.

• Direct HIF regulators inhibit the interaction between HIF-1α and p300 without affecting levels of HIF-1α protein.

• Some HIF inhibitors are under pre- and early clinical development as anticancer agents.

This box summarizes key points contained in the article.

Financial and competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.