Small molecule screen identifies pyrimethamine as an inhibitor of NRF2-driven esophageal hyperplasia.

ABSTRACT:

Objective

NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2^high ESCC.

Design

We performed high-throughput screening of two compound libraries from which hit compounds were further validated in human ESCC cells and a genetically modified mouse model. The mechanism of action of one compound was explored by biochemical assays.

Results

Using high-throughput screening of two small molecule compound libraries, we identified 11 hit compounds as potential NRF2 inhibitors with minimal cytotoxicity at specified

SUBMITTER: Paiboonrungruang C 

PROVIDER: S-EPMC10558795 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature