Recent progress in the development of small molecule Nrf2 modulators: a patent review (2012-2016)

ABSTRACT

Introduction: The NF-E2-related factor-2 (Nrf2) is a critical transcription factor that regulates the expression of many phase II and antioxidant genes to maintain the homeostasis. It has many biological functions and plays a central role in the cellular defensive machinery. The abnormal regulation of Nrf2 is closely associated with multiple diseases.

Areas covered: This article first discusses the molecular regulatory mechanism of Nrf2-antioxidant response element (ARE) signaling. Then patents and publications about Nrf2 activators and inhibitors from 2012–2016 are reviewed. Several case studies are emphasized to introduce the molecular design strategy, especially on Keap1-Nrf2 protein-protein interaction (PPI) inhibitor.

Expert opinion: Firstly, new chemotypes of Nrf2 modulators can be designed in a combination of the progress of both covalent modifiers and target selective Keap1-Nrf2 interaction inhibitors. The aim is to balance the activity and toxicity of Nrf2 modulators. Secondly, considering many known Nrf2 activators, such as DMF and SFN, are electrophilic entities with very small molecular weight, we need to update the concept of how to recognize a drug candidate. Finally, per the mechanism of the Nrf2 modulator, compounds with the most active Nrf2 inductivity maybe not the best choice for the design of an ideal chemopreventive agent.

KEYWORDS:

• Nrf2 modulators
• covalent activators
• protein-protein interaction
• Nrf2 inhibitors
• small molecules

Article highlights

• Nrf2-ARE signaling plays a central role in the cellular defensive mechanism by regulating the expression of many phase II and antioxidant genes.

• The regulatory mechanism of Nrf2-ARE signaling under normal condition or electrophilic/oxidative stress is discussed to show the modulator design strategy.

• Dimethyl fumarate, a known Nrf2 activator, has been approved for the treatment of multiple sclerosis, indicating the promising medical use of Nrf2 modulators.

• Many Nrf2 activators with different mechanisms and structures are disclosed, providing various lead compounds for designing novel therapeutic agents targeting Nrf2-ARE signaling.

• Keap1-Nrf2 PPI inhibitor is a class of non-electrophilic Nrf2 activator that is anticipated to be more selective and safe than electrophilic compounds. Several compounds exhibit very high potency in blocking Keap1-Nrf2 interaction. Case studies in this article show the importance of structure-based molecular design in the identification of Keap1-Nrf2 PPI inhibitors.

• Discovering Nrf2 inhibitors recently attracts the attention of researchers with the aim to overcome the dark side effect of Nrf2 in protecting cancer cells. Several compounds have shown their potential in enhancing the sensitivity of cancer cells to chemo- or radiotherapy.

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Declaration of interest

The authors have no other 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 apart from those disclosed.

Additional information

Funding

Financial support from National Natural Science Foundation of China (81402851 and 81573281) and Fundamental Research Funds for the Central Universities (2015ZD009) are gratefully acknowledged.