Recent progress in the development of small molecule Nrf2 activators: a patent review (2017-present)

ABSTRACT

Introduction: The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is the first line of defense against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of Nrf2 is a potential therapeutic approach for several diseases related to oxidative stress and inflammation, such as cancer, cardiovascular, and neurodegenerative diseases.

Areas covered: The authors first describe the biological function of Nrf2 and the molecular regulatory mechanism of Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1)-Nrf2-(antioxidant response element)). Then, they review recent progress of covalent activators and non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitors from patents and publications in 2017-present, consisting of new chemical molecules, structure optimization of reported activators and progress in preclinical or clinical trials.

Expert opinion: Despite significant achievements in the development of Nrf2 activators, the selectivity is the primary consideration. Due to reacting with redox-sensitive cysteines in proteins except for Keap1, electrophilic activators often exhibit off-target effects. For Keap1-Nrf2 PPI inhibitors, how to enhance in vivo efficacy and/or penetrate blood-brain barrier (BBB) to reach central nervous system (CNS) is also challenging. Fragment-based drug discovery (FBDD), carboxylic acid bioisosteric replacement and prodrug approach might be used to circumvent this challenge. Moreover, the possibility of cancer risk caused by Nrf2 activation needs to be considered carefully.

KEYWORDS:

• Nrf2 activators
• Keap1
• ARE
• covalent activators
• PPI inhibitors

Article highlights

• The Keap1-Nrf2-ARE pathway plays a critical role in the cellular defense system and its dysregulation relates to many diseases.

• The detailed regulatory mechanism of Keap1-Nrf2-ARE signaling is discussed.

• Dimethyl fumarate, Sulforaphane, Bardoxolone methyl, and some of their derivatives are undergoing various preclinical or clinical trials. Many other types of covalent Nrf2 activators have also been identified.

• Directly disrupting Keap1-Nrf2 PPI has been an effective strategy to activate Nrf2. Compared with covalent Nrf2 activators, non-covalent Keap1-Nrf2 PPI inhibitors may activate Nrf2 with reduced toxic risk.

• Lots of Keap1-Nrf2 PPI inhibitors have been reported, and some of them have achieved high potency. Selected case studies in this article show the discovery and development of Keap1-Nrf2 PPI inhibitors.

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

This study was supported by Projects 81773581, 81773639, and 81930100 of the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province of China (no. BK20160746), National Science & Technology Major Project ‘Key New Drug Creation and Manufacturing Program’, China (no. 2018ZX09711002 and 2017ZX09302003), the Priority Academic Program Development of Jiangsu Higher Education Institutions, CPU2018GY02 of Double First Class Innovation Team of China Pharmaceutical University, Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education, the ‘Qing Lan’ Project of Jiangsu Province, and the Young Elite Scientists Sponsorship Program by CAST.