PMID- 27552339
OWN - NLM
STAT- MEDLINE
DCOM- 20170622
LR  - 20231104
IS  - 1554-8937 (Electronic)
IS  - 1554-8929 (Print)
IS  - 1554-8929 (Linking)
VI  - 11
IP  - 11
DP  - 2016 Nov 18
TI  - Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in 
      KEAP1-Deficient NSCLC Tumors.
PG  - 3214-3225
AB  - Loss of function mutations in Kelch-like ECH Associated Protein 1 (KEAP1), or 
      gain-of-function mutations in nuclear factor erythroid 2-related factor 2 (NRF2), 
      are common in non-small cell lung cancer (NSCLC) and associated with therapeutic 
      resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted 
      a quantitative high-throughput screen using a diverse set of  approximately 400 000 small 
      molecules (Molecular Libraries Small Molecule Repository Library, MLSMR) at the 
      National Center for Advancing Translational Sciences. We identified ML385 as a 
      probe molecule that binds to NRF2 and inhibits its downstream target gene 
      expression. Specifically, ML385 binds to Neh1, the Cap 'N' Collar Basic Leucine 
      Zipper (CNC-bZIP) domain of NRF2, and interferes with the binding of the V-Maf 
      Avian Musculoaponeurotic Fibrosarcoma Oncogene Homologue G (MAFG)-NRF2 protein 
      complex to regulatory DNA binding sequences. In clonogenic assays, when used in 
      combination with platinum-based drugs, doxorubicin or taxol, ML385 substantially 
      enhances cytotoxicity in NSCLC cells, as compared to single agents. ML385 shows 
      specificity and selectivity for NSCLC cells with KEAP1 mutation, leading to gain 
      of NRF2 function. In preclinical models of NSCLC with gain of NRF2 function, 
      ML385 in combination with carboplatin showed significant antitumor activity. We 
      demonstrate the discovery and validation of ML385 as a novel and specific NRF2 
      inhibitor and conclude that targeting NRF2 may represent a promising strategy for 
      the treatment of advanced NSCLC.
FAU - Singh, Anju
AU  - Singh A
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University , Baltimore, Maryland 21205, United States.
FAU - Venkannagari, Sreedhar
AU  - Venkannagari S
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University , Baltimore, Maryland 21205, United States.
FAU - Oh, Kyu H
AU  - Oh KH
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University , Baltimore, Maryland 21205, United States.
FAU - Zhang, Ya-Qin
AU  - Zhang YQ
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Rohde, Jason M
AU  - Rohde JM
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Liu, Li
AU  - Liu L
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Nimmagadda, Sridhar
AU  - Nimmagadda S
AD  - Departments of Radiology and Oncology, School of Medicine, Johns Hopkins 
      University , Baltimore, Maryland 21205, United States.
FAU - Sudini, Kuladeep
AU  - Sudini K
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University , Baltimore, Maryland 21205, United States.
FAU - Brimacombe, Kyle R
AU  - Brimacombe KR
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Gajghate, Sachin
AU  - Gajghate S
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University , Baltimore, Maryland 21205, United States.
FAU - Ma, Jinfang
AU  - Ma J
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University , Baltimore, Maryland 21205, United States.
FAU - Wang, Amy
AU  - Wang A
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Xu, Xin
AU  - Xu X
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Shahane, Sampada A
AU  - Shahane SA
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Xia, Menghang
AU  - Xia M
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Woo, Juhyung
AU  - Woo J
AD  - Department of Oncology, School of Medicine, Johns Hopkins University , Baltimore, 
      Maryland 21205, United States.
FAU - Mensah, George A
AU  - Mensah GA
AD  - Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and 
      Health Sciences , Worcester, Massachusetts 01608, United States.
FAU - Wang, Zhibin
AU  - Wang Z
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University , Baltimore, Maryland 21205, United States.
FAU - Ferrer, Marc
AU  - Ferrer M
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Gabrielson, Edward
AU  - Gabrielson E
AD  - Department of Oncology, School of Medicine, Johns Hopkins University , Baltimore, 
      Maryland 21205, United States.
FAU - Li, Zhuyin
AU  - Li Z
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Rastinejad, Fraydoon
AU  - Rastinejad F
AD  - Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research 
      Institute , Orlando, Florida 32827, United States.
FAU - Shen, Min
AU  - Shen M
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Boxer, Matthew B
AU  - Boxer MB
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health , Rockville, Maryland 20850, United States.
FAU - Biswal, Shyam
AU  - Biswal S
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University , Baltimore, Maryland 21205, United States.
AD  - Department of Oncology, School of Medicine, Johns Hopkins University , Baltimore, 
      Maryland 21205, United States.
LA  - eng
GR  - Z01 HG200319-05/Intramural NIH HHS/United States
GR  - R03 MH092170/MH/NIMH NIH HHS/United States
GR  - R01 CA206155/CA/NCI NIH HHS/United States
GR  - P50 CA058184/CA/NCI NIH HHS/United States
GR  - R01 CA140492/CA/NCI NIH HHS/United States
GR  - R01 ES025761/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20161017
PL  - United States
TA  - ACS Chem Biol
JT  - ACS chemical biology
JID - 101282906
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
SB  - IM
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology
MH  - Cell Line, Tumor
MH  - *Drug Resistance, Neoplasm
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/*genetics
MH  - Lung Neoplasms/*drug therapy/metabolism/pathology
MH  - NF-E2-Related Factor 2/*antagonists & inhibitors
PMC - PMC5367156
MID - NIHMS852206
EDAT- 2016/10/18 06:00
MHDA- 2017/06/24 06:00
PMCR- 2017/03/27
CRDT- 2016/08/24 06:00
PHST- 2016/10/18 06:00 [pubmed]
PHST- 2017/06/24 06:00 [medline]
PHST- 2016/08/24 06:00 [entrez]
PHST- 2017/03/27 00:00 [pmc-release]
AID - 10.1021/acschembio.6b00651 [doi]
PST - ppublish
SO  - ACS Chem Biol. 2016 Nov 18;11(11):3214-3225. doi: 10.1021/acschembio.6b00651. 
      Epub 2016 Oct 17.