Focal adhesion kinase (FAK) is a tyrosine kinase overexpressed in cancer cells. Especially, FAK plays an important role in the progression of tumors to a malignant phenotype. FAK associates with integrins and modulates various cellular processes including growth, survival, and migration. In particular, PND-1186 is a substituted pyridine reversible inhibitor of FAK activity with an IC₅₀ of 1.5 nM in vitro.

In the tumor microenvironment, nuclear FAK can regulate the formation of new blood vessels, affecting the tumor blood supply. PND-1186 has an IC₅₀ of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. Moreover, PND-1186 blocks FAK and p130Cas tyrosine phosphorylation promotes caspase-3 activation and triggers cell apoptosis. PND-1186 inhibits 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activations. Particularly, PND-1186 has an IC₅₀ of 1.5 nM to recombinant FAK and ~0.1 µM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. Furthermore, PND-1186 inhibits breast carcinoma cell motility in a dose-dependent fashion.

PND-1186 inhibits 4T1 subcutaneous tumor growth and is associated with tumor cell apoptosis. In addition, PND-1186 functions as a potent preventative and/or prophylactic anti-tumor agent. Increasing concentrations of PND-1186 (0.1 to 1.0 µM) added to 4T1 cells inhibit FAK Tyr-397 phosphorylation (pY397) and result in elevated levels of total FAK protein within 1 h. Besides, PND-1186 inhibits 4T1 spheroid growth and FAK-p130Cas phosphorylation in suspension.

Taken together, FAK can affect the growth of cancer stem cells through this mechanism of the regulation of cell stiffness. Ultimately, PND-1186 potently inhibits FAK phosphorylation in a reversible manner.