Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Bab-Al-Mouadam, Baghdad, 10001, Iraq.
Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan.
Curr Med Chem. 2024;31(38):6336-6356. doi: 10.2174/0109298673305163240427065543.
Allosteric inhibition of EGFR tyrosine kinase (TK) is currently among the most attractive approaches for designing and developing anti-cancer drugs to avoid chemoresistance exhibited by clinically approved ATP-competitive inhibitors. The current work aimed to synthesize new biphenyl-containing derivatives that were predicted to act as EGFR TK allosteric site inhibitors based on molecular docking studies.
A new series of 4'-hydroxybiphenyl-4-carboxylic acid derivatives, including hydrazine-1-carbothioamide (S3-S6) and 1,2,4-triazole (S7-S10) derivatives, were synthesized and characterized using IR, HNMR, CNMR, and HR-mass spectroscopy.
Compound S4 had a relatively high pharmacophore-fit score, indicating that it may have biological activity similar to the EGFR allosteric inhibitor reference, and it scored a relatively low ΔG against EGFR TK allosteric site, indicating a high likelihood of drug-receptor complex formation. Compound S4 was cytotoxic to the three cancer cell lines tested, particularly HCT-116 colorectal cancer cells, with an IC value comparable to Erlotinib. Compound S4 induced the intrinsic apoptotic pathway in HCT-116 cells by arresting them in the G2/M phase. All of the new derivatives, including S4, met the requirements for EGFR allosteric inhibitory activity.
Compound S4 is a promising EGFR tyrosine kinase allosteric inhibitor that warrants further research.
目前，针对表皮生长因子受体（EGFR）酪氨酸激酶（TK）的变构抑制作用，是设计和开发抗癌药物的最有吸引力的方法之一，可避免临床批准的 ATP 竞争性抑制剂所表现出的化疗耐药性。本研究旨在根据分子对接研究，合成新的含联苯结构的衍生物，预测其可作为 EGFR TK 的变构位点抑制剂。
我们合成了一系列新的 4'-羟基联苯-4-羧酸衍生物，包括肼-1-碳硫酰胺（S3-S6）和 1,2,4-三唑（S7-S10）衍生物，并通过红外光谱（IR）、核磁共振氢谱（1H-NMR）、核磁共振碳谱（13C-NMR）和高分辨质谱（HR-MS）进行了结构表征。
化合物 S4 的药效团拟合分数相对较高，表明其可能具有与 EGFR 变构抑制剂参考物相似的生物学活性，且与 EGFR TK 变构位点的ΔG 值相对较低，表明药物-受体复合物形成的可能性较高。S4 对三种测试的癌细胞系均具有细胞毒性，尤其是对结直肠癌细胞 HCT-116，其 IC 值与厄洛替尼相当。S4 通过将 HCT-116 细胞阻滞在 G2/M 期，诱导其发生内在凋亡途径。所有新的衍生物，包括 S4，均满足 EGFR 变构抑制活性的要求。
化合物 S4 是一种有前途的 EGFR 酪氨酸激酶变构抑制剂，值得进一步研究。
