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Non-Covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation

52 Pages Posted: 15 Mar 2019 Sneak Peek Status: Review Complete

See all articles by Shasha Tao

Shasha Tao

University of Arizona - Department of Pharmacology and Toxicology

Wang Tian

University of Arizona - Department of Pharmacology and Toxicology

Joseph Tillotson

University of Arizona - Department of Pharmacology and Toxicology

E. M. Kithsiri Wijeratne

University of Arizona - Natural Products Center

A. A. Leslie Gunatilaka

University of Arizona - Natural Products Center

Donna D. Zhang

University of Arizona - Department of Pharmacology and Toxicology

Eli Chapman

University of Arizona - Department of Pharmacology and Toxicology

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Abstract

The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation. Currently, nearly all NRF2 inducers are electrophilic molecules that possess unwanted off-target effects due to their reactive nature. Here, we report a group of NRF2 inducers, ent-kaurane diterpenoid geopyxins, with and without C151 reactive electrophilic moieties. Among 16 geopyxins, geopyxin F, a non-electrophilic NRF2 activator, showed enhanced cellular protection relative to an electrophilic NRF2 activator, geopyxin C. To our knowledge, this represents the first detailed structure activity relationship study of covalent versus non-covalent NRF2 activators, showing the promise of non-covalent NRF2 activators as potential therapeutic compounds.

Keywords: NRF2, chemoprevention, geopyxin, natural product, drug discovery

Suggested Citation

Tao, Shasha and Tian, Wang and Tillotson, Joseph and Wijeratne, E. M. Kithsiri and Gunatilaka, A. A. Leslie and Zhang, Donna D. and Chapman, Eli, Non-Covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation (March 14, 2019). Available at SSRN: https://ssrn.com/abstract=3352498 or http://dx.doi.org/10.2139/ssrn.3352498
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Shasha Tao

University of Arizona - Department of Pharmacology and Toxicology

Tucson, AZ 85721
United States

Wang Tian

University of Arizona - Department of Pharmacology and Toxicology

Tucson, AZ 85721
United States

Joseph Tillotson

University of Arizona - Department of Pharmacology and Toxicology

Tucson, AZ 85721
United States

E. M. Kithsiri Wijeratne

University of Arizona - Natural Products Center

Tucson, AZ 85721
United States

A. A. Leslie Gunatilaka

University of Arizona - Natural Products Center

Tucson, AZ 85721
United States

Donna D. Zhang

University of Arizona - Department of Pharmacology and Toxicology ( email )

Tucson, AZ 85721
United States

Eli Chapman (Contact Author)

University of Arizona - Department of Pharmacology and Toxicology ( email )

Tucson, AZ 85721
United States

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