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

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Abstract
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.
Funding Information
  • National Cancer Institute (R01CA148706)
  • NIH Office of the Director (S10OD010678-01)
  • National Institute of General Medical Sciences (R16GM154786)
  • Middle Tennessee State University

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