Discovery and Design of NRF2 Modulators

Nuclear factor erythroid 2–related factor 2, or NRF2, is a key protein responsible for the regulation of numerous signaling pathways in the body, particularly those related to oxidative stress and cytokine release. As such, reduced NRF2 activity has been identified as a contributing factor of numerous inflammatory and mitochondrial diseases. The majority of current small molecule NRF2 activators are electrophilic in nature, a characteristic that may explain the prevalence of dangerous off-target effects related to these compounds. In an effort to avoid these complications, non-electrophilic compound PRL-295 was developed. Though PRL-295 has proven to be an effective NRF2 activator in-vitro, optimization of the compound’s pharmacokinetic properties is essential to extend this effectiveness to an array of tissue types in-vivo, and I have synthesized a series of prodrugs in an effort to achieve this. Simultaneously, I am using high throughput screening to discover additional molecules that induce NRF2 activation to a similar or increased degree compared to PRL-295. Due to its mitigation of oxidative stress, excessive NRF2 activation may prevent cells with damaged genetic material from undergoing apoptosis and has been implicated in carcinogenesis. In order to address this, I have used high throughput screening in an effort to discover small molecule NRF2 activity inhibitors, particularly those which stabilize the protein-protein interaction between NRF2 and its native modulator KEAP1, promoting ubiquitination and degradation. The identification of such a compound would constitute the identification of a novel NRF2 inhibition mechanism, expanding the range of approaches to cancer treatment.

Author dc:creator

• Tatum Johnson (16859992)

• NRF2
• KEAP1

Statement dc:rights

• In Copyright
• Open Access after 2028-05-01

DOI dc:identifier

https://doi.org/10.25417/uic.32995148.v1

OAI identifier oai:identifier

oai:figshare.com:article/32995148