School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana-Monroe, Monroe, LA 71209-0497, USA.
Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy.
Bioorg Chem. 2021 Feb;107:104595. doi: 10.1016/j.bioorg.2020.104595. Epub 2020 Dec 30.
Due to hurdles, including resistance, adverse effects, and poor bioavailability, among others linked with existing therapies, there is an urgent unmet need to devise new, safe, and more effective treatment modalities for skin cancers. Herein, a series of flavonol-based derivatives of fisetin, a plant-based flavonoid identified as an anti-tumorigenic agent targeting the mammalian targets of rapamycin (mTOR)-regulated pathways, were synthesized and fully characterized. New potential inhibitors of receptor tyrosine kinases (c-KITs), cyclin-dependent kinase-2 (CDK2), and mTOR, representing attractive therapeutic targets for melanoma and non-melanoma skin cancers (NMSCs) treatment, were identified using inverse-docking, in vitro kinase activity and various cell-based anticancer screening assays. Eleven compounds exhibited significant inhibitory activities greater than the parent molecule against four human skin cancer cell lines, including melanoma (A375 and SK-Mel-28) and NMSCs (A431 and UWBCC1), with IC values ranging from 0.12 to < 15 μM. Seven compounds were identified as potentially potent single, dual or multi-kinase c-KITs, CDK2, and mTOR kinase inhibitors after inverse-docking and screening against twelve known cancer targets, followed by kinase activity profiling. Moreover, the potent compound F20, and the multi-kinase F9 and F17 targeted compounds, markedly decreased scratch wound closure, colony formation, and heightened expression levels of key cancer-promoting pathway molecular targets c-Kit, CDK2, and mTOR. In addition, these compounds downregulated Bcl-2 levels and upregulated Bax and cleaved caspase-3/7/8 and PARP levels, thus inducing apoptosis of A375 and A431 cells in a dose-dependent manner. Overall, compounds F20, F9 and F17, were identified as promising c-Kit, CDK2 and mTOR inhibitors, worthy of further investigation as therapeutics, or as adjuvants to standard therapies for the control of melanoma and NMSCs.
由于现有疗法存在耐药性、不良反应和生物利用度差等障碍，因此迫切需要设计新的、安全的、更有效的皮肤癌治疗方法。在此，我们合成并充分表征了一系列基于榭皮素的类黄酮衍生物，榭皮素是一种植物来源的类黄酮，被鉴定为一种针对哺乳动物雷帕霉素靶蛋白（mTOR）调控途径的抗肿瘤剂。使用反向对接、体外激酶活性和各种基于细胞的抗癌筛选测定法，鉴定了新的受体酪氨酸激酶（c-KIT）、细胞周期蛋白依赖性激酶-2（CDK2）和 mTOR 的潜在抑制剂，它们是治疗黑色素瘤和非黑色素瘤皮肤癌（NMSC）的有吸引力的治疗靶点。11 种化合物对四种人皮肤癌细胞系（包括黑色素瘤（A375 和 SK-Mel-28）和 NMSC（A431 和 UWBCC1））表现出显著的抑制活性，其 IC 值范围为 0.12 至 <15μM。七种化合物被鉴定为潜在有效的单、双或多激酶 c-KIT、CDK2 和 mTOR 激酶抑制剂，它们在针对 12 种已知癌症靶点进行反向对接和筛选后，通过激酶活性分析进行鉴定。此外，强效化合物 F20 和多激酶靶向化合物 F9 和 F17 显著降低划痕伤口闭合、集落形成，并显著降低促进癌症的关键分子靶标 c-Kit、CDK2 和 mTOR 的表达水平。此外，这些化合物下调 Bcl-2 水平，上调 Bax 和切割的 caspase-3/7/8 和 PARP 水平，从而以剂量依赖性方式诱导 A375 和 A431 细胞凋亡。总体而言，化合物 F20、F9 和 F17 被鉴定为有前途的 c-Kit、CDK2 和 mTOR 抑制剂，值得进一步研究作为治疗剂，或作为标准疗法的辅助剂，以控制黑色素瘤和 NMSC。
