Constitutive activation of STAT3 plays an important role in the development of melanoma; an aggressive form of skin cancer. Therefore, STAT3 inhibitors are potential chemotherapeutic agents for melanoma. We designed and synthesized a series of variably substituted quinolone-incorporating 1,2,4-triazole/oxime hybrids. Their anti-proliferative activity was determined at the National Cancer Institute (NCI). Six compounds showed promising anti-proliferative activity in several tested cell lines. Three of them were evaluated further to assess their ability to suppress STAT3 activation in four melanoma cell lines. The tested compounds showed a robust ability to inhibit STAT3 phosphorylation at Tyr705 and Ser727; the essential amino acid residues involved in STAT3 activation. For example, 10 µM of <b>7b</b> effectively inhibited STAT3 phosphorylation in the melanoma cell lines and completely abrogated its transcriptional activity at 50 µM concentration. Further development of the compounds discovered in this study may produce more potent and selective STAT3 inhibitors.

Novel quinoline-incorporating 1,2,4-triazole/oxime hybrids inhibit STAT3 phosphorylation and suppress human melanoma cell growth

255th National Meeting (2018)

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