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

Abstract

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.

Bioengineered NRF2-siRNA Is Effective to Interfere with NRF2 Pathways and Improve Chemosensitivity of Human Cancer Cells

“…Although NRF2 represents a promising therapeutic target for the treatment of cancer, current RNA interference (RNAi) materials are limited to synthetic small interfering RNAs (siRNAs) or shRNAexpressing agents (Singh et al, 2008;Fourtounis et al, 2012;Lu et al, 2016), in addition to small-molecule modulators that might not be very potent or selective (Sun et al, 2017). Utilization of shRNA-expressing agents (e.g., viral or nonviral vector-based systems) may complicate RNAi processes because they are literally DNA materials that rely on not only the efficiency of gene delivery but also the capacity of host cells or organisms in transcribing DNA to noncoding RNAs (ncRNAs) before the execution of siRNA actions.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…These patents are protecting chalcone derivatives, novel amide triterpenoid derivatives, deuteriumsubstituted fumarate derivatives, 3-alkylamino-1H-indolyl acrylate derivatives, withanolide, a benzyl derivative containing an activated vinyl group, andrographolide or [S] + apomorphine, and sesquiterpene lactone derivative (Sun et al, 2017). Although most of these compounds proved to be useful to some degree from a preclinical proof-of-concept perspective, their clinical value is to date generally very limited.…”

“…They exhibit Michael acceptor activity through its a-b unsaturated scaffold and represent the most potent inducers of NRF2 (Sun et al, 2017). They interact with C151 of KEAP1 and impede its interaction with CUL3, hence leading to NRF2 activation (Cleasby et al, 2014).…”

“…Therefore, DMF is currently used as the first line of treatment of relapsing-remitting MS that cannot be treated by traditional therapies. New formulations of DMF are being tested and patented to improve drug bioavailability and efficacy (Sun et al, 2017). For instance, MMF has been used to develop a second generation of NRF2 inducers as prodrugs (Zeidan et al, 2014).…”

Current Status and Challenges of NRF2 as a Potential Therapeutic Target for Diabetic Cardiomyopathy

“…13) New formulations of DMF are being tested to improve the drug bioavailability and efficacy. 82) These new formulations of DMF may have potential to use in the clinical trial of DCM. 83) Rutin: Rutin is a flavonol.…”