Authors
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 Gabrielson, Zhuyin Li, Fraydoon Rastinejad, Min Shen, Matthew B Boxer, Shyam Biswal
Publication date
2016/11/18
Journal
ACS chemical biology
Volume
11
Issue
11
Pages
3214-3225
Publisher
American Chemical Society
Description
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 …
Scholar articles
A Singh, S Venkannagari, KH Oh, YQ Zhang… - ACS chemical biology, 2016