Discovery of novel pyrrolo [2,3-d] pyrimidine derivatives as potent FAK inhibitors based on cyclization strategy.

ABSTRACT

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a pivotal role in tumor invasion and metastasis. Many FAK inhibitors had been reported, but the development of FAK inhibitors in clinical studies are still limited. To facilitate the discovery of FAK modulators and further elucidate the role of FAK in cancer metastasis, it is necessary to discover a novel, potent and selective FAK inhibitor. In this study, a series of FAK inhibitors with novel scaffold were designed and synthesized based on cyclization strategy. Here, we reported compound 10b (HMC-18NH) with excellent inhibition of FAK (IC50 = 9.9 nM) and anticancer activity against several cancer cell lines including BxPC-3, PANC-1, MCF-7, MDA-MB-231, U-87MG, HepG2, HCT-15 and A549. Extraordinary, compound 10b showed the best cytotoxic effects against A549 with the IC50 value of 0.8 µM. In addition, 10b exhibited effective invasion and migration suppression in A549 cells. Further investigations revealed that compound 10b potently induced and promoted apoptosis in a dose-dependent manner and arrested A549 cells in the G2/M phase. Collectively, these results suggest that 10b is a promising FAK inhibitor and serve as a lead compound which deserve for further optimization.