An updated patent review of Nrf2 activators (2020-present)

ABSTRACT

Introduction

The nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor that controls the expression of numerous cytoprotective genes and regulates cellular defense system against oxidative insults. Thus, activating the Nrf2 pathway is a promising strategy for the treatment of various chronic diseases characterized by oxidative stress.

Areas covered

This review first discusses the biological effects of Nrf2 and the regulatory mechanism of Kelch-like ECH-associated protein 1-Nrf2-antioxidant response element (Keap1-Nrf2-ARE) pathway. Then, Nrf2 activators (2020-present) are summarized based on the mechanism of action. The case studies consist of chemical structures, biological activities, structural optimization, and clinical development.

Expert opinion

Extensive efforts have been devoted to developing novel Nrf2 activators with improved potency and drug-like properties. These Nrf2 activators have exhibited beneficial effects in in vitro and in vivo models of oxidative stress-related chronic diseases. However, some specific problems, such as target selectivity and brain blood barrier (BBB) permeability, still need to be addressed in the future.

KEYWORDS:

• ARE
• chronic diseases
• electrophilic activators
• Keap1
• Nrf2 activators
• protein–protein interaction inhibitors

Article highlights

• The Nrf2-ARE pathway exerts a crucial role in counteracting oxidative insults and maintaining cellular homeostasis. Activating the Nrf2-ARE pathway is a promising therapeutic strategy for many oxidative stress-related chronic diseases.

• Nrf2 activators are classified by the mechanism of action.

• Many types of electrophilic Nrf2 activators are currently undergoing preclinical or clinical trials for new clinical indications.

• Directly inhibiting the Keap1-Nrf2 PPI provides an alternative strategy to activate Nrf2. The case studies show the importance of various medicinal chemistry design strategies in the discovery of Keap1-Nrf2 inhibitors.

• Disrupting the interaction between β-TrCP and Nrf2 offers another approach to activate Nrf2.

• Great progress has been made in the development of Nrf2 activators, especially in Keap1-Nrf2 inhibitors, which offers both opportunities and challenges for future research.

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.

Author contribution statement

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Additional information

Funding

This paper was funded by the National Science Foundation of China (82173680 and 81930100), Jiangsu Province Funds for Distinguished Young Scientists (Grant BK20220087) and the young Elite Scientists Sponsorship Program by CAST (No. YESS20180146, China).