Design, synthesis, and biological evaluation of novel FAK scaffold inhibitors targeting the FAK–VEGFR3 protein–protein interaction

•Structure activity relationship of FAK–VEGFR3 inhibitor C4.•Evaluated novel C4 analogs by molecular modeling and in vitro biological activity.•Heteroaromatic and 4-chlorobenzyl groups are critical for activity.•Discovery of compound 29 showing enhanced potency and selectivity for target site.

Focal adhesion kinase (FAK) and vascular endothelial growth factor receptor 3 (VEGFR3) are tyrosine kinases, which function as key modulators of survival and metastasis signals in cancer cells. Previously, we reported that small molecule chlorpyramine hydrochloride (C4) specifically targets the interaction between FAK and VEGFR3 and exhibits anti-tumor efficacy. In this study, we designed and synthesized a series of 1 (C4) analogs on the basis of structure activity relationship and molecular modeling. The resulting new compounds were evaluated for their binding to the FAT domain of FAK and anti-cancer activity. Amongst all tested analogs, compound 29 augmented anti-proliferative activity in multiple cancer cell lines with stronger binding to the FAT domain of FAK and disrupted the FAK–VEGFR3 interaction. In conclusion, we hope that this work will contribute to further studies of more potent and selective FAK–VEGFR3 protein–protein interaction inhibitors.

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