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Novel Triazoloquinoxaline-Based Tubulin Polymerization Inhibitor Induces Necroptosis and Significantly Inhibits
Christopher J Clark1,2, Shelby N Waddell3, Garrett E Tessmer4
1Department of Chemistry, Middle Tennessee State University, Murfreesboro, Tennessee 37132, United States.
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.
Insights
Researchers developed novel triazoloquinoxaline compounds to treat metastatic melanoma. The most potent compound, 9d, effectively inhibited melanoma cell growth and tumor progression in mice, inducing apoptosis and necroptosis.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Metastatic melanoma is a deadly skin cancer, causing 80% of skin cancer deaths.
- Colchicine-binding site inhibitors show preclinical promise for metastatic and paclitaxel-resistant melanoma.
Purpose of the Study:
- To design, synthesize, and evaluate novel triazoloquinoxaline-based compounds for melanoma treatment.
- To identify potent analogs with therapeutic potential against melanoma.
Main Methods:
- Synthesis and biological evaluation of 35 novel triazoloquinoxaline compounds.
- In vitro antiproliferative assays, cell cycle analysis, and apoptosis induction studies.
- In vivo efficacy and safety studies in a B16-F10 syngeneic mouse model.
Main Results:
- Compound 9d exhibited potent antiproliferative activity (GI50 = 15.4 nM against A375) and bound to the colchicine site.
- In vitro, 9d induced G2/M cell cycle arrest and apoptosis.
- In vivo, 9d (10 mg/kg) showed a good safety profile, inhibited tumor growth, and induced apoptosis and necroptosis.
Conclusions:
- Novel triazoloquinoxaline compound 9d demonstrates significant therapeutic potential for metastatic melanoma.
- Compound 9d possesses a unique dual mechanism of inducing both apoptosis and necroptosis in melanoma cells.
- Further investigation of 9d as a melanoma therapeutic is warranted.
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