A patent review on hypoxia-inducible factor (HIF) modulators (2021-2023)

ABSTRACT

Introduction

Hypoxia-inducible factor (HIF) is a central regulatory factor in detecting and adapting to cellular oxygen stress. Dysregulation of HIF is associated with various human diseases. Seven HIF modulators, including six prolyl hydroxylase (PHD) inhibitors and one HIF-2α inhibitor, have already been approved for the treatment of renal anemia and cancer, respectively.

Areas covered

This review summarizes HIF modulators patented in the 2021-2023 period. This review provides an overview of HIF downregulators, including HIF-1α inhibitors, HIF-2α inhibitors, and HIF-2α degraders, as well as HIF upregulators, including PHD, FIH, and VHL inhibitors, and HIF-2α and HIF-3α agonists.

Expert opinion

Efforts should be made to address the adverse clinical effects associated with approved HIF-modulating drugs, including PHD inhibitors and HIF-2α inhibitors. Identification of the specific buried cavity in the HIF-2α and an opened pocket in HIF-3α offer an avenue for designing novel modulators for HIF-2α or HIF-3α. Given the similarities observed in the binding cavities of HIF-2α and HIF-3α, it should be considered whether the approved HIF-2α inhibitors also inhibit HIF-3α. A comprehensive understanding of the HIF signaling pathway biology would lead to the development of novel small-molecule HIF modulators as innovative therapeutic approaches for a wide range of human diseases.

KEYWORDS:

• HIF inhibitor
• PHD inhibitor
• FIH inhibitor
• VHL inhibitor
• HIF agonist

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Article highlights

1. HIF is a central biological molecule in the cellular oxygen-sensing signal pathway.

2. Structures and mechanisms of HIF modulators are described throughout.

c. Only one HIF inhibitor has been approved, with numerous HIF inhibitors currently in clinical and pre-clinical stages.

d. Numerous HIF upregulators are in stages of clinical and pre-clinical research.

e. Six PHD inhibitors have been approved to date.

f. Challenges and opportunities for improving HIF modulators in the near future.

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

A reviewer on this manuscript has disclosed that they are an inventor on some previous patents relevant to the pathway. They have also received honoraria for talking at meetings organised by AstraZeneca. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was funded by grants from the National Natural Science Foundation of China (Grants 82273769 and 82322062), Jiangsu Province Funds for Distinguished Young Scientists (Grant BK20211527), and China Pharmaceutical University.