Exploring Thieno/Furo[2,3-b]pyridines as new scaffolds for potential FAK inhibition: Design, synthesis, biological evaluation and in silico studies

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a vital role in regulating cancer cell survival, proliferation, migration, and angiogenesis. Aiming to explore new potent inhibitors, a series of thieno/furo[2,3-b]pyridine derivatives was designed and synthesized. The newly synthesized compounds were evaluated for their in vitro anti-proliferative activity against human liver (HUH-7), lung (A549) and breast (MCF-7) cancer cell lines, in addition to their cytotoxic activity against normal lung cell line (WI-38) to predict their safety profile. Seven compounds (4a, 4c, 5, 6, 10c, 11 and 12) displayed significant anti-proliferative activity as well as high selectivity towards the tested cancer cell lines (SI > 2). Among them, two compounds (4a and 4c) potently inhibited FAK enzyme with IC₅₀ values of 54.96 and 50.98 nM, respectively. Flow cytometric cell cycle analysis indicated that compounds 4a and 4c caused cell cycle arrest at G1 phase. Compound 4c also exhibited an increase in the expression level of caspase-3 enzyme. Moreover, molecular docking study of the most promising compounds into FAK's active site was performed to elucidate their possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors.