Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors

Anju Singh, Sreedhar Venkannagari, Kyu H. Oh, Ya Qin Zhang, Jason M. Rohde, Li Liu, Sridhar Nimmagadda, Kuladeep Sudini, Kyle R. Brimacombe, Sachin Gajghate, Jinfang Ma, Amy Wang, Xin Xu, Sampada A. Shahane, Menghang Xia, Juhyung Woo, George A. Mensah, Zhibin Wang, Marc Ferrer, Edward GabrielsonZhuyin Li, Fraydoon Rastinejad, Min Shen, Matthew B. Boxer, Shyam Biswal

Research output: Contribution to journalArticle

Abstract

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 ∼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.

Original languageEnglish (US)
Pages (from-to)3214-3225
Number of pages12
JournalACS Chemical Biology
Volume11
Issue number11
DOIs
StatePublished - Nov 18 2016

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Non-Small Cell Lung Carcinoma
Tumors
Small Molecule Libraries
Erythroid-Specific DNA-Binding Factors
Molecules
Leucine Zippers
Neoplasms
Proteins
Carboplatin
Mutation
Cytotoxicity
Paclitaxel
Platinum
Gene expression
Doxorubicin
Assays
Therapeutics
Cells
Throughput
Fibrosarcoma

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. / Singh, Anju; Venkannagari, Sreedhar; Oh, Kyu H.; Zhang, Ya Qin; Rohde, Jason M.; Liu, Li; Nimmagadda, Sridhar; Sudini, Kuladeep; Brimacombe, Kyle R.; Gajghate, Sachin; Ma, Jinfang; Wang, Amy; Xu, Xin; Shahane, Sampada A.; Xia, Menghang; Woo, Juhyung; Mensah, George A.; Wang, Zhibin; Ferrer, Marc; Gabrielson, Edward; Li, Zhuyin; Rastinejad, Fraydoon; Shen, Min; Boxer, Matthew B.; Biswal, Shyam.

In: ACS Chemical Biology, Vol. 11, No. 11, 18.11.2016, p. 3214-3225.

Research output: Contribution to journalArticle

Singh, A, Venkannagari, S, Oh, KH, Zhang, YQ, Rohde, JM, Liu, L, Nimmagadda, S, Sudini, K, Brimacombe, KR, Gajghate, S, Ma, J, Wang, A, Xu, X, Shahane, SA, Xia, M, Woo, J, Mensah, GA, Wang, Z, Ferrer, M, Gabrielson, E, Li, Z, Rastinejad, F, Shen, M, Boxer, MB & Biswal, S 2016, 'Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors', ACS Chemical Biology, vol. 11, no. 11, pp. 3214-3225. https://doi.org/10.1021/acschembio.6b00651
Singh, Anju ; Venkannagari, Sreedhar ; Oh, Kyu H. ; Zhang, Ya Qin ; Rohde, Jason M. ; Liu, Li ; Nimmagadda, Sridhar ; Sudini, Kuladeep ; Brimacombe, Kyle R. ; Gajghate, Sachin ; Ma, Jinfang ; Wang, Amy ; Xu, Xin ; Shahane, Sampada A. ; Xia, Menghang ; Woo, Juhyung ; Mensah, George A. ; Wang, Zhibin ; Ferrer, Marc ; Gabrielson, Edward ; Li, Zhuyin ; Rastinejad, Fraydoon ; Shen, Min ; Boxer, Matthew B. ; Biswal, Shyam. / Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. In: ACS Chemical Biology. 2016 ; Vol. 11, No. 11. pp. 3214-3225.
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abstract = "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 ∼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.",
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AU - Singh, Anju

AU - Venkannagari, Sreedhar

AU - Oh, Kyu H.

AU - Zhang, Ya Qin

AU - Rohde, Jason M.

AU - Liu, Li

AU - Nimmagadda, Sridhar

AU - Sudini, Kuladeep

AU - Brimacombe, Kyle R.

AU - Gajghate, Sachin

AU - Ma, Jinfang

AU - Wang, Amy

AU - Xu, Xin

AU - Shahane, Sampada A.

AU - Xia, Menghang

AU - Woo, Juhyung

AU - Mensah, George A.

AU - Wang, Zhibin

AU - Ferrer, Marc

AU - Gabrielson, Edward

AU - Li, Zhuyin

AU - Rastinejad, Fraydoon

AU - Shen, Min

AU - Boxer, Matthew B.

AU - Biswal, Shyam

PY - 2016/11/18

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N2 - 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 ∼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.

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