Albalawi Fatemah S, Bhat Mashooq A, Bakheit Ahmed H, Rahman A F M Motiur, Alsaif Nawaf A, Jones Alan M, Romero-Canelon Isolda
School of Pharmacy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Pharmaceuticals (Basel). 2025 Jul 17;18(7):1051. doi: 10.3390/ph18071051.
The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, - (,), as anticancer agents targeting EGFR and HER2 kinases. The proposed compounds were initially screened in silico using molecular docking to investigate their binding affinity to the active sites of EGFR and HER2 kinase domains. Subsequently, the compounds were synthesized and evaluated in vitro for their antiproliferative activity, using the MTT assay, against the various cancer cell lines A549, SKOV-3, A2780, and SKBR-3, with lapatinib as the reference drug. The most active derivatives were then examined to determine their inhibitory activity against EGFR and HER2 kinases. Among the assessed compounds, significant antiproliferative activity was demonstrated by , , and . exhibited substantial anticancer efficacy against A549 and SKBR-3, with IC values of 0.81 µM and 1.41 µM, respectively. This activity surpassed lapatinib, which has an IC of 11.57 µM on A549 and 8.54 µM on SKBR-3 cells. Furthermore, , , and exhibited superior EGFR inhibitory efficacy compared with lapatinib (IC = 0.13 µM), with IC values of 0.08, 0.06, and 0.07 µM, respectively. Regarding HER2, demonstrated the greatest potency with an IC of 0.03 µM, equipotent to lapatinib (IC = 0.03 µM). Flow cytometry analysis of A549 cells treated with and indicated their ability to arrest the cell cycle during the G1 phase and to trigger cellular apoptosis. Compounds , , and represent intriguing candidates for the development of an anticancer agent targeting EGFR and HER2 kinases.
表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2）的双重靶向是癌症治疗的一种有效方法。当前研究涉及一系列新型含嘌呤腙类化合物（，，）作为靶向EGFR和HER2激酶的抗癌剂的设计、合成及生物学评价。最初通过分子对接在计算机上对所提出的化合物进行筛选，以研究它们与EGFR和HER2激酶结构域活性位点的结合亲和力。随后，合成这些化合物并使用MTT法在体外针对多种癌细胞系A549、SKOV - 3、A2780和SKBR - 3评估其抗增殖活性，以拉帕替尼作为参考药物。然后对活性最强的衍生物进行检测，以确定它们对EGFR和HER2激酶的抑制活性。在所评估的化合物中，，和表现出显著的抗增殖活性。对A549和SKBR - 3表现出显著的抗癌疗效，IC值分别为0.81 μM和1.41 μM。这种活性超过了拉帕替尼，拉帕替尼对A549的IC值为11.57 μM，对SKBR - 3细胞的IC值为8.54 μM。此外，，和与拉帕替尼（IC = 0.13 μM）相比表现出更强的EGFR抑制效力，IC值分别为0.08、0.06和0.07 μM。关于HER2，表现出最大的效力，IC值为0.03 μM，与拉帕替尼相当（IC = 0.03 μM）。用和处理的A549细胞的流式细胞术分析表明它们能够使细胞周期停滞在G1期并触发细胞凋亡。化合物，和是开发靶向EGFR和HER2激酶的抗癌剂的有趣候选物。
