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  3. Synthesis and biological evaluation of 1-phenyl-tetrahydro-β-carboline-based first dual PRMT5/EGFR inhibitors as potential anticancer agents

Synthesis and biological evaluation of 1-phenyl-tetrahydro-β-carboline-based first dual PRMT5/EGFR inhibitors as potential anticancer agents

  • Eur J Med Chem. 2024 Mar 18:269:116341. doi: 10.1016/j.ejmech.2024.116341.
Juan Zhang 1,  Xuliang Liu 2,  Na Sa 2,  Jin-He Zhang 3,  Yong-Si Cai 3,  Kai-Ming Wang 3,  Wei Xu 4,  Cheng-Shi Jiang 5,  Kong-Kai Zhu 6
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, 250012, China.
  • 3 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China.
  • 4 Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, 250012, China. Electronic address: xuwhns@126.com.
  • 5 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China. Electronic address: bio_jiangcs@ujn.edu.cn.
  • 6 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: hkhhh.k@163.com.
PMID: 38518523 DOI: 10.1016/j.ejmech.2024.116341
Abstract

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 IC50 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 IC50 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.

Keywords

1-Phenyl-tetrahydro-β-carboline (THβC) derivative; Antitumor activity; EGFR inhibitor; PRMT5 inhibitor; Pharmacokinetic profiles.

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