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

2 Scopus citations

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

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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

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