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Expert Opin Ther Pat. 2020 Jan 10. doi: 10.1080/13543776.2020.1715365. [Epub ahead of print]

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

Zhou H1,2, Wang Y1,2, You Q1,2, Jiang Z1,2.

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State Key Laboratory of Natural Medicines, and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, TongJiaXiang 24, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, TongJiaXiang 24, Nanjing 210009, China.


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.


ARE; Keap1; Nrf2 activators; PPI inhibitors; covalent activators

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