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

This study reports the rational design and systematic evaluation of a novel series of 2-substituted aniline pyrimidine derivatives as dual Mer/c-Met inhibitors. Among the synthesized compounds, 17c demonstrated potent dual kinase inhibition, with IC₅₀ values of 6.4 ± 1.8 nM (Mer) and 26.1 ± 7.7 nM (c-Met). The compound exhibited significant antiproliferative activity across multiple cancer cell lines (HepG2, MDA-MB-231, and HCT116), while showing minimal hERG channel inhibition (IC₅₀ > 40 μM), indicating favorable cardiac safety. Pharmacokinetic profiling revealed high metabolic stability in human liver microsomes (t_1/2 = 53.1 min) and moderate oral bioavailability (<i>F</i>: 45.3%), with strong plasma protein-binding affinity (>95%). Mechanistic studies further demonstrated that 17c dose-dependently suppressed HCT116 cell migration and induced apoptosis. These integrated pharmacological properties position 17c as a promising therapeutic candidate for dual Mer/c-Met drive malignancies.