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

  • J Med Chem. 2026 Mar 26;69(6):6461-6489. doi: 10.1021/acs.jmedchem.5c02226.
Christopher J Clark  1  2 ,  Shelby N Waddell  3 ,  Garrett E Tessmer  4 ,  Carl B Womack  4 ,  Yang Xie  3 ,  Brittney D Williams  4 ,  Meirola A Endraws  4 ,  Cole T Huddleston  4 ,  Keiluhn D Pulis  4 ,  Joshua Thammathong  1 ,  Kamil Tanas  1 ,  Beari A Jangir  1 ,  Dejian Ma  3 ,  Kevin L Bicker  1  2 ,  Yaohong Wang  5 ,  April M Weissmiller  2  4 ,  Wei Li  3 ,  Souvik Banerjee  1  2
Affiliations
  • 1. Department of Chemistry, Middle Tennessee State University, Murfreesboro, Tennessee 37132, United States.
  • 2. Molecular Biosciences Program, Middle Tennessee State University, Murfreesboro, Tennessee 37132, United States.
  • 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 4. Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee 37132, United States.
  • 5. Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, United States.
PMID: 41808012 DOI: 10.1021/acs.jmedchem.5c02226
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.

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