Novel Triazoloquinoxaline-Based Tubulin Polymerization Inhibitor Induces Necroptosis and Significantly Inhibits Metastatic Melanoma Tumor Growth

Metastatic melanoma is the deadliest form of skin cancer, being responsible for 80% of skin cancer deaths. Small molecule colchicine-binding site inhibitors have previously demonstrated preclinical therapeutic efficacy in treating metastatic and paclitaxel-resistant melanoma. We report here on the design, synthesis, and biological evaluation of thirty-five novel triazoloquinoxaline-based compounds with promising therapeutic potential. The most potent analog, 9d, showed strong antiproliferative activity against a panel of melanoma cell lines (GI50 = 15.4 nM against A375) and binds to the colchicine site. Treatment with 9d in vitro arrests the cell cycle in the G2/M phase and induces apoptosis. In vivo, compound 9d (10 mg/kg) demonstrated a good safety profile, significantly inhibited tumor growth and proliferation, and induced leukocyte infiltration along with apoptosis and necroptosis in an immunocompetent B16–F10 syngeneic mouse model. Further evaluation of 9d has characterized its unique mechanism of inducing both apoptosis and necroptosis in treated melanoma cells.