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
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
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 - NRF2
KW - cancer
KW - chemoprevention
KW - drug discovery
KW - geopyxin
KW - natural product
KW - non-covalent
KW - structure activity relationship
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U2 - 10.1016/j.chembiol.2019.07.011
DO - 10.1016/j.chembiol.2019.07.011
M3 - Article
C2 - 31402317
AN - SCOPUS:85073059741
SN - 2451-9456
VL - 26
SP - 1427-1435.e5
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 10
ER -