Green Chemistry Department, Chemical Industries Research Division, National Research Center P.O. Box 12622, Egypt; Molecular Modelling Lab., Biochemistry School, Bristol University, Bristol, UK.
Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
Bioorg Med Chem Lett. 2020 Dec 15;30(24):127658. doi: 10.1016/j.bmcl.2020.127658. Epub 2020 Oct 29.
Human epidermal growth factor receptor (HER) is a family of multidomain proteins that plays important role in the regulation of several biological functions. HER2 is a member of HER that is highly presented in breast cancer cells. Here, we designed and synthesized a series of diaryl urea/thiourea compounds. The compounds were tested on HER2 breast cancer cells including MCF-7 and SkBr3, compared to HER2 breast cancer cells including MDA-MB-231 and BT-549. Only compounds 12-14 at 10 µM showed selective anti-proliferative activity against MCF-7 and SkBr3 by 65-79%. Compounds 12-14 showed >80% inhibition of the intracellular kinase domain of HER2. The results obtained indicated that compounds 12-14 are selectively targeting HER2 cells. The IC of compound 13 against MCF-7 and SkBR3 were 1.3 ± 0.009 and 0.73 ± 0.03 µM, respectively. Molecular docking and MD simulations (50 ns) were carried out, and their binding free energies were calculated. Compounds 12-14 formed strong hydrogen bond and pi-pi stacking interactions with the key residues Thr862 and Phe864. 3DQSAR model confirmed the role of 3-bromo substituent of pyridine ring and 4-chloro substituent of phenyl ring in the activity of the compounds. In conclusion, novel compounds, particularly 13 were developed selectively against HER2-expressing/overexpressing breast cancer cells including MCF7 and SkBr3.
人表皮生长因子受体（HER）是一组多功能蛋白，在调节多种生物学功能中发挥重要作用。HER2 是 HER 家族的成员，在乳腺癌细胞中高度表达。在这里，我们设计并合成了一系列二芳基脲/硫脲化合物。将这些化合物在包括 MCF-7 和 SkBr3 的 HER2 阳性乳腺癌细胞以及包括 MDA-MB-231 和 BT-549 的 HER2 阴性乳腺癌细胞中进行了测试。只有化合物 12-14 在 10µM 时对 MCF-7 和 SkBr3 显示出 65-79%的选择性抗增殖活性。化合物 12-14 对 HER2 细胞内激酶结构域的抑制率超过 80%。结果表明，化合物 12-14 选择性地靶向 HER2 细胞。化合物 13 对 MCF-7 和 SkBR3 的 IC 分别为 1.3±0.009 和 0.73±0.03µM。进行了分子对接和 MD 模拟（50ns），并计算了它们的结合自由能。化合物 12-14 与关键残基 Thr862 和 Phe864 形成了强氢键和 pi-pi 堆积相互作用。3DQSAR 模型证实了吡啶环上的 3-溴取代基和苯基环上的 4-氯取代基在化合物活性中的作用。总之，特别是化合物 13，针对表达/过表达 HER2 的乳腺癌细胞（包括 MCF7 和 SkBr3）开发出了新型化合物。
