Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, 250012, China; School of Biological Science and Technology, University of Jinan, Jinan, 250022, China.
Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, 250012, China.
Eur J Med Chem. 2024 Apr 5;269:116341. doi: 10.1016/j.ejmech.2024.116341. Epub 2024 Mar 18.
Protein arginine methyltransferase 5 (PRMT5) and epidermal growth factor receptor (EGFR) are both involved in the regulation of various cancer-related processes, and their dysregulation or overexpression has been observed in many types of tumors. In this study, we designed and synthesized a series of 1-phenyl-tetrahydro-β-carboline (THβC) derivatives as the first class of dual PRMT5/EGFR inhibitors. Among the synthesized compounds, 10p showed the most potent dual PRMT5/EGFR inhibitory activity, with IC values of 15.47 ± 1.31 and 19.31 ± 2.14 μM, respectively. Compound 10p also exhibited promising antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines, with IC values below 10 μM. Molecular docking studies suggested that 10p could bind to PRMT5 and EGFR through hydrophobic, π-π, and cation-π interactions. Furthermore, 10p displayed favorable pharmacokinetic properties and oral bioavailability (F = 30.6%) in rats, and administrated orally 10p could significantly inhibit the growth of MCF7 orthotopic xenograft tumors. These results indicate that compound 10p is a promising hit compound for the development of novel and effective dual PRMT5/EGFR inhibitors as potential anticancer agents.
蛋白质精氨酸甲基转移酶 5（PRMT5）和表皮生长因子受体（EGFR）都参与了多种与癌症相关过程的调节，并且在许多类型的肿瘤中观察到它们的失调或过表达。在这项研究中，我们设计并合成了一系列 1-苯基-四氢-β-咔啉（THβC）衍生物，作为第一类双重 PRMT5/EGFR 抑制剂。在所合成的化合物中，10p 表现出最强的双重 PRMT5/EGFR 抑制活性，其 IC 值分别为 15.47 ± 1.31 和 19.31 ± 2.14 μM。化合物 10p 还对 A549、MCF7、HeLa 和 MDA-MB-231 细胞系表现出有希望的抗增殖活性，IC 值低于 10 μM。分子对接研究表明，10p 可以通过疏水、π-π 和阳离子-π 相互作用与 PRMT5 和 EGFR 结合。此外，10p 在大鼠中表现出良好的药代动力学特性和口服生物利用度（F = 30.6%），口服给予 10p 可显著抑制 MCF7 原位异种移植肿瘤的生长。这些结果表明，化合物 10p 是开发新型有效双重 PRMT5/EGFR 抑制剂作为潜在抗癌药物的有前途的命中化合物。
