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
  • 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: [email protected].
  • 5. School of Biological Science and Technology, University of Jinan, Jinan, 250022, China. Electronic address: [email protected].
  • 6. Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: [email protected].
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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