Nrf2 Inhibitors for the Enhancement of Cancer Chemotherapy and Radiotherapy

This technology includes the identification of small molecule inhibitors of nuclear factor erythroid-2 related factor-2 (Nrf2) as therapeutic anticancer agents. Multiple mechanisms lead to frequent dysregulation of Nrf2 activity in cancer cells, which promotes both tumorigenesis and therapeutic resistance. Dysregulated Nrf2-Keap1 pathway is a novel determinant of chemoresistance/radioresistance and inhibition of Nrf2 signaling will enhance the efficacy of chemotherapeutic and radiotherapy. Based on their potency, specificity and tractability, we have selected 3 compounds for bulk synthesis and screening additional analogues. These compounds belonging to three different structural classes showed direct inhibition of DNA binding activity of Nrf2-MAF complex and were validated as specific inhibitors using a Fluorescence Polarization assay. In combination with platinum-based chemotherapy, these compounds significantly enhanced inhibition compared with single agent in clonogenic assay. These 3 compounds have been resynthesized and their activity as Nrf2 inhibitors has been confirmed using the aforementioned assays.