1 research outputs found
Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors
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