The design and synthesis of highly efficient FAK inhibitor for the potential treatment of colorectal cancer harboring KRAS mutation.

Herein, a series of 2-arylaminopyrimidine derivatives were designed and synthesized as new type of Focal adhesion kinase (FAK) inhibitors. Among them, 7g, as a promising compound, demonstrated a strong combining capability to FAK with a half-maximal inhibitory concentration (IC50) of 10.87 nM, and displayed effective antiproliferative activities against colorectal cells HCT116 (IC50 = 0.460 μM) in vitro.

The results of the pharmacokinetics showed that 7g presented acceptable bioavailability with an F value of 26.91%.

Furthermore, 7g exhibited statistical difference for inhibition of tumor growth in HCT116 cells xenograft model compared to the control group with TGI value of 66.5% under the dosage of 90 mg/kg. The analysis of the mechanism of action validated that 7g promoted cell apoptosis in a certain of degree by blocking the cell cycle at the G2/M phase and arresting the activity of FAK-AKT signal pathway.

Moreover, the fluorescence analysis indicated that the proportion of Ki67 positive cells in colorectal cancer organoid decreased after exposing with 7g. In addition, 7g did not result significant hepatotoxicity, nephrotoxicity during the in vivo experimental period.