The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU38225. By inhibiting production of antioxidants, MSU38225 increases the level of reactive oxygen species (ROS) when cells are stimulated with tert-butyl hydroperoxide (tBHP). MSU38225 also inhibits the growth of human lung cancer cells in both two-dimensional cell culture and soft agar. Cancer cells addicted to Nrf2 are more susceptible to MSU38225 for suppression of cell proliferation. MSU38225 also sensitizes human lung cancer cells to chemotherapies both in vitro and in vivo. Our results suggest that MSU38225 is a novel Nrf2 pathway inhibitor that could potentially serve as an adjuvant therapy to enhance the response to chemotherapies in patients with lung cancer.

Metal quinoline complexes were prepared using a quinoline-based proteasome inhibitor (Quin1) and an inactive quinoline ligand (Quin2), and their cytotoxicities are reported towards multiple myeloma-related cell lines.

SAR on NRF2 inhibitor MSU38225 has led to a compound that inhibits expression of NRF2 target genes, reduces proliferation of lung cancer cells through G2/M arrest, and lowers cell migration.

<div>Abstract<p>The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in <i>NFE2L2, KEAP1</i>, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU38225. By inhibiting production of antioxidants, MSU38225 increases the level of reactive oxygen species (ROS) when cells are stimulated with tert-butyl hydroperoxide (tBHP). MSU38225 also inhibits the growth of human lung cancer cells in both two-dimensional cell culture and soft agar. Cancer cells addicted to Nrf2 are more susceptible to MSU38225 for suppression of cell proliferation. MSU38225 also sensitizes human lung cancer cells to chemotherapies both <i>in vitro</i> and <i>in vivo</i>. Our results suggest that MSU38225 is a novel Nrf2 pathway inhibitor that could potentially serve as an adjuvant therapy to enhance the response to chemotherapies in patients with lung cancer.</p></div>

<p>Suppl Fig. 1 lists the primer sequences for NFE2L2 and downstream gene targets of Nrf2. Suppl Fig. 2 shows that MSU38225 does not alter the overall expression pattern of abundant cellular proteins. Suppl Fig. 3 shows that MSU38225 does not inhibit the proliferation of MCF10A cells at concentrations that inhibit the Nrf2 pathway.</p>