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

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Dysregulation of PRMT5 and EGFR is implicated in various cancers.
• Targeting both PRMT5 and EGFR offers a potential strategy for novel cancer therapies.

Purpose of the Study:

• To design and synthesize novel 1-phenyl-tetrahydro-β-carboline (THβC) derivatives as dual PRMT5/EGFR inhibitors.
• To evaluate the in vitro and in vivo anticancer efficacy of these compounds.

Main Methods:

• Synthesis of THβC derivatives.
• In vitro enzyme inhibition assays for PRMT5 and EGFR.
• Cell-based antiproliferative assays against multiple cancer cell lines.
• Molecular docking studies to predict binding interactions.
• Pharmacokinetic studies and in vivo efficacy evaluation in xenograft models.

Main Results:

• Compound 10p emerged as a potent dual PRMT5/EGFR inhibitor with IC50 values in the low micromolar range.
• 10p exhibited significant antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines.
• Molecular docking indicated favorable binding interactions of 10p with PRMT5 and EGFR.
• 10p demonstrated good oral bioavailability and efficacy in inhibiting MCF7 tumor growth in vivo.

Conclusions:

• Compound 10p represents a promising hit compound for developing novel dual PRMT5/EGFR inhibitors.
• These findings support the potential of 10p as an anticancer agent.