Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2016–2020)

ABSTRACT

Introduction: Hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis. The increased expression of genes targeted by HIF is associated with many human diseases, including ischemic cardiovascular disease, stroke, chronic lung disease, and cancer.

Areas covered: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years.

Expert opinion: HIF inhibitors have shown promise for the treatment of hypoxic pulmonary hypertension, a circadian rhythm disorder, calcific aortic valve disease, cerebrovascular accident, and heterotopic ossification. In addition, HIF-2α inhibitors can be used for the treatment or prevention of iron overload disorders, Crohn’s disease, ulcerative colitis, and thyroid eye disease, or to improve muscle generation and repair. PT2385 completed phase I clinical trials for the treatment of clear cell renal cell carcinoma. It exerted a higher synergistic inhibitory effect on tumor growth in combination with anti–PD-1 antibody, in comparison with each treatment alone, indicating that effective immunotherapy for solid tumors counteracts of the immunosuppression induced by hypoxia. Therefore, considering the effects of hypoxia on cancer cells, stromal cells, and effector immune cells, it is important to develop inhibitors of molecular pathways activated by hypoxia for successful treatments.

KEYWORDS:

• Cancer
• hypoxia-inducible factor (HIF)
• HIF inhibitors
• oxygen-regulation
• microenvironment
• immunosuppression

Article highlights

1. HIF is a major regulator of oxygen homeostasis and is involved in many human diseases.

2. Various HIF-1α and HIF-2α inhibitors have been developed, and some of them are in clinical trials for the treatment of cancers.

3. Many therapeutic uses of HIF-1α and HIF-2α inhibitors for HIF-related diseases have been reported.

This box summarizes key points contained in the article.

Declaration of interest

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

A part of this study was supported by a grant from the KRIBB Research Initiative Program.