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 IC₅₀ 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）是一个多域蛋白家族，在调节几种生物学功能中起重要作用。HER2是在乳腺癌细胞中高度存在的HER成员。在这里，我们设计并合成了一系列的二芳基脲/硫脲化合物。将化合物于HER2测试⁺乳腺癌细胞，包括MCF-7和SKBR3，相比HER2 ^-乳腺癌细胞，包括MDA-MB-231和BT-549。仅10 µM的化合物12–14对MCF-7和SkBr3表现出65-79％的选择性抗增殖活性。化合物12-14对HER2的细胞内激酶结构域显示出大于80％的抑制作用。获得的结果表明，化合物12-14选择性靶向HER2 ⁺细胞。IC ₅₀针对MCF-7和SkBR3的化合物13的摩尔数分别为1.3±0.009和0.73±0.03 µM。进行了分子对接和MD模拟（50 ns），并计算了它们的结合自由能。化合物12-14与重要残基Thr862和Phe864形成强氢键和pi-pi堆积相互作用。3DQSAR模型证实了吡啶环的3-溴取代基和苯环的4-氯取代基在化合物活性中的作用。总之，选择性地开发了新型化合物，特别是13种化合物，用于对抗表达HER2 /过表达的乳腺癌细胞，包括MCF7和SkBr3。