Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States.
Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, United States.
Eur J Med Chem. 2022 Apr 15;234:114229. doi: 10.1016/j.ejmech.2022.114229. Epub 2022 Mar 10.
In our continued SAR study efforts, a series of O-alkylamino-tethered salicylamide derivatives with various amino acid linkers has been designed, synthesized, and biologically evaluated as potent anticancer agents. Five selected compounds with different representative chemical structures were found to show broad anti-proliferative activities, effective against all tested ER-positive breast cancer (BC) and triple-negative breast cancer (TNBC) cell lines with low micromolar IC values. Among these compounds, compound 9a (JMX0293) maintained good potency against MDA-MB-231 cell line (IC = 3.38 ± 0.37 μM) while exhibiting very low toxicity against human non-tumorigenic breast epithelial cell line MCF-10A (IC > 60 μM). Further mechanistic studies showed that compound 9a could inhibit STAT3 phosphorylation and contribute to apoptosis in TNBC MDA-MB-231 cells. More importantly, compound 9a significantly suppressed MDA-MB-231 xenograft tumor growth in vivo without significant toxicity, indicating its great potential as a promising anticancer drug candidate for further clinical development.
在我们持续的 SAR 研究努力中，设计、合成并评估了一系列具有各种氨基酸连接子的 O-烷氨基甲酰基水杨酰胺衍生物，作为有效的抗癌药物。发现具有不同代表性化学结构的 5 种选定化合物具有广泛的抗增殖活性，对所有测试的 ER 阳性乳腺癌（BC）和三阴性乳腺癌（TNBC）细胞系均有效，IC 值低至微摩尔。在这些化合物中，化合物 9a（JMX0293）对 MDA-MB-231 细胞系保持良好的活性（IC = 3.38 ± 0.37 μM），而对人非肿瘤性乳腺上皮细胞系 MCF-10A 的毒性非常低（IC > 60 μM）。进一步的机制研究表明，化合物 9a 可以抑制 STAT3 磷酸化并促进 TNBC MDA-MB-231 细胞凋亡。更重要的是，化合物 9a 显著抑制 MDA-MB-231 异种移植瘤在体内的生长而没有明显的毒性，表明其作为有前途的抗癌药物候选物具有很大的潜力，可进一步进行临床开发。
