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

Pengfei Liu, Wang Tian, Shasha Tao, Joseph Tillotson, E. M.Kithsiri Wijeratne, A. A.Leslie Gunatilaka, Donna D. Zhang, Eli Chapman

Research output: Contribution to journalArticle

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 is 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.

Original languageEnglish (US)
Pages (from-to)1427-1435.e5
JournalCell Chemical Biology
Volume26
Issue number10
DOIs
StatePublished - Oct 17 2019

Fingerprint

Ubiquitin-Protein Ligases
Kaurane Diterpenes
Chemical activation
Degradation
Diterpenes
Ubiquitination
Structure-Activity Relationship
Oxidants
Oxidation-Reduction
Cysteine
Homeostasis
Transcription Factors
Molecules
Substrates
Proteins
Therapeutics
Kelch-Like ECH-Associated Protein 1

Keywords

  • cancer
  • chemoprevention
  • drug discovery
  • geopyxin
  • natural product
  • non-covalent
  • NRF2
  • structure activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation. / Liu, Pengfei; Tian, Wang; Tao, Shasha; Tillotson, Joseph; Wijeratne, E. M.Kithsiri; Gunatilaka, A. A.Leslie; Zhang, Donna D.; Chapman, Eli.

In: Cell Chemical Biology, Vol. 26, No. 10, 17.10.2019, p. 1427-1435.e5.

Research output: Contribution to journalArticle

Liu, Pengfei ; Tian, Wang ; Tao, Shasha ; Tillotson, Joseph ; Wijeratne, E. M.Kithsiri ; Gunatilaka, A. A.Leslie ; Zhang, Donna D. ; Chapman, Eli. / Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation. In: Cell Chemical Biology. 2019 ; Vol. 26, No. 10. pp. 1427-1435.e5.
@article{6312833329da4da49410779186aeb421,
title = "Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation",
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 is 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 = "cancer, chemoprevention, drug discovery, geopyxin, natural product, non-covalent, NRF2, structure activity relationship",
author = "Pengfei Liu and Wang Tian and Shasha Tao and Joseph Tillotson and Wijeratne, {E. M.Kithsiri} and Gunatilaka, {A. A.Leslie} and Zhang, {Donna D.} and Eli Chapman",
year = "2019",
month = "10",
day = "17",
doi = "10.1016/j.chembiol.2019.07.011",
language = "English (US)",
volume = "26",
pages = "1427--1435.e5",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "10",

}

TY - JOUR

T1 - Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation

AU - Liu, Pengfei

AU - Tian, Wang

AU - Tao, Shasha

AU - Tillotson, Joseph

AU - Wijeratne, E. M.Kithsiri

AU - Gunatilaka, A. A.Leslie

AU - Zhang, Donna D.

AU - Chapman, Eli

PY - 2019/10/17

Y1 - 2019/10/17

N2 - 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 is 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.

AB - 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 is 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.

KW - cancer

KW - chemoprevention

KW - drug discovery

KW - geopyxin

KW - natural product

KW - non-covalent

KW - NRF2

KW - structure activity relationship

UR - http://www.scopus.com/inward/record.url?scp=85073059741&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073059741&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2019.07.011

DO - 10.1016/j.chembiol.2019.07.011

M3 - Article

C2 - 31402317

AN - SCOPUS:85073059741

VL - 26

SP - 1427-1435.e5

JO - Cell Chemical Biology

JF - Cell Chemical Biology

SN - 2451-9448

IS - 10

ER -