Discovery of Novel 2-Substituted Aniline Pyrimidine Based Derivatives as Potent Mer/c-Met Dual Inhibitors with...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Mer and c-Met kinases are critical targets in various malignancies.
• Developing dual inhibitors offers a strategy to overcome resistance and improve efficacy.
• Novel chemical scaffolds are needed for effective kinase inhibition.

Purpose of the Study:

• To design and synthesize novel 2-substituted aniline pyrimidine derivatives.
• To evaluate their potential as dual inhibitors of Mer and c-Met kinases.
• To assess the antiproliferative activity and safety profile of lead compounds.

Main Methods:

• Rational drug design and chemical synthesis of pyrimidine derivatives.
• In vitro kinase inhibition assays (IC50 determination for Mer and c-Met).
• Antiproliferative assays in cancer cell lines (HepG2, MDA-MB-231, HCT116).
• hERG channel inhibition assays for cardiac safety assessment.
• Pharmacokinetic studies (metabolic stability, oral bioavailability, protein binding).
• Mechanistic studies including cell migration and apoptosis assays.

Main Results:

• Compound 17c exhibited potent dual inhibition of Mer (IC50 = 6.4 nM) and c-Met (IC50 = 26.1 nM).
• 17c demonstrated significant antiproliferative activity against HepG2, MDA-MB-231, and HCT116 cancer cell lines.
• Favorable safety profile with minimal hERG channel inhibition (IC50 > 40 μM).
• Pharmacokinetic studies showed high metabolic stability (t1/2 = 53.1 min), moderate oral bioavailability (F = 45.3%), and high protein binding (>95%).
• Mechanistic studies confirmed dose-dependent suppression of HCT116 cell migration and induction of apoptosis.

Conclusions:

• Compound 17c is a potent dual Mer/c-Met inhibitor with significant anticancer efficacy.
• The favorable safety and pharmacokinetic profile of 17c supports its therapeutic potential.
• 17c represents a promising drug candidate for treating malignancies driven by Mer/c-Met signaling.