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.
Agent to circumvent therapeutic resistance and enhance the efficacy of chemotherapy and radiotherapy in the treatment of cancer.
First-in-class; currently, there are no known direct pharmacological inhibitors of Nrf2.