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Discovery of novel, potent, small molecule inhibitors of nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated gene transcription for the treatment of cancer

Wednesday, November 06, 2013 — Poster Session I

4:00 p.m. – 6:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • J. Rohde
  • Y. Zhang
  • A. Singh
  • L. Liu
  • S. Venkannagari
  • N. Thorne
  • M. Ferrer
  • Z. Li
  • M. Shen
  • S. Biswal
  • M. Boxer


Nuclear factor erythroid-2 related factor 2 (Nrf2) is an important transcription factor which controls the expression of a number of electrophile and xenobiotic detoxification enzymes and efflux proteins, which provide cytoprotection against oxidative stress and apoptosis in normal cells. Many cancer cells show marked increase in Nrf2 activity and a resultant increase in the expression of these drug detoxification enzymes and efflux pumps conferring both chemotherapeutic resistance and radioresistance. Herein, we describe the quantitative high throughput screening of the MLPCN compound library for inhibitors of the Nrf2 pathway and the ensuing medicinal chemistry optimization of the small molecule hits. These compounds will help to understand Nrf2-mediated gene expression in both cytoprotective and cancer biology. The Nrf2 inhibitors which have emerged from this effort display both clonogenic and in vivo A549 lung cancer xenograft model activity and show efficacy as single agents and in combination with carboplatin. In addition to serving as tool compounds for Nrf2-mediated biology, we believe that these molecules may lead to new and improved oncology treatments.

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