Discovery of novel 2,4-diarylaminopyrimidine derivatives as FAK inhibitors with potent anti-cancer potency.

AIM: To evaluate novel 2,4-diarylaminopyrimidine derivatives as FAK inhibitors for cancer therapy and investigate their antitumor activity and mechanism of action.

MATERIALS AND

METHODS

A series of derivatives (D1-D15) was designed and synthesized by incorporating a hydrazone unit into the TAE-226 scaffold. Kinase assays were performed to assess FAK inhibitory potency and selectivity. Antiproliferative activity against human cancer cell lines was evaluated via MTT assay. Molecular docking and dynamics simulations analyzed the binding modes. Mechanistic studies, including Western blot, colony formation, migration, and flow cytometry assays, were conducted in KYSE30 and KYSE150 esophageal cancer cells.

RESULTS

Compound D12 potently inhibited FAK (IC50 = 67.22 nM) with significantly improved selectivity over Pyk2, ALK, and EGFR compared to TAE-226. D12 exhibited broad-spectrum antiproliferative activity across multiple cancer cell lines, with particular potency against esophageal KYSE30 (IC50 = 25.64 nM), gastric MGC-803 (IC50 = 33.72 nM), and ovarian PA-1 (IC50 = 28.77 nM) cells. Mechanistically, compound D12 effectively suppressed FAK phosphorylation and downstream MAPK/ERK and AKT/mTOR signaling, leading to inhibition of colony formation, migration, cell cycle progression, and induction of apoptosis.

CONCLUSION

Compound D12 is a novel FAK inhibitor with improved selectivity and potent antitumor activity, representing a promising lead candidate for cancer therapy.