Yeni izoksazol türevlerinin antitümör etkilerinin araştırılması ve biyotin konjugasyonunun bu etkiler üzerindeki rolü

Cancer remains one of the deadliest diseases worldwide. Despite current advancements in the cancer therapeutics, cancer will be global health challenge. Therefore, there is need for development of more effective alternative cancer therapeutics. In this context, here, we evaluated potential of isoxazole-based compounds in cancer therapeutics. In addition to parental isoxazole based-compound EB38, in our study we included biotinylated forms of EB38 (namely compound 160 and compound 161) to assess how biotin conjugation contributes to efficacy of anticancer compounds. To this end, we conducted proliferation assays in 2D cancer models, characterized their pro-apoptotic capacity biochemically, and recapitulated our findings in 3D spheroid models. To investigate the safety of the compounds we used zebrafish larvae to perform toxicity test. We found that EB38 induces anti-proliferative and pro-apoptotic effects in cancer cell lines and more importantly these effects were potentiated with biotin conjugation of compounds. Moreover, we mechanistically identified JAK/STAT pathway as target of EB38 and its biotinylated derivatives. Additionally, we conducted experiments to understand through which routes biotinylated compounds are accumulated within cells and proposed that alternative, non-competitive mechanism that is not mediated by SMVT might regulate uptake of the biotinylated compounds. These findings suggest that EB38 and its derivatives hold potential for anticancer therapy and that biotin conjugation can serve as a strategy to enhance their therapeutic efficiency.