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

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.PMID:38518523 | DOI:10.1016/j.ejmech.2024.116341
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research