Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy

Abstract

FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through “proteolysis targeting chimera” (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents.

FAK Shutdown: Consequences on Epithelial Morphogenesis and Biomarker Expression Involving an Innovative Biomaterial for Tissue Regeneration

“…Thus, it seems plausible that different cell types show a specific response to the mode of FAK inactivation and that the amount of the final FAK activity strongly depends on the exact biological context [ 88 ]. It will be interesting to further study the differences of pharmacological and siRNA-based FAK inhibition in different tissues and situations of cellular interaction since FAK abrogation is a promising concept for future cancer therapies, whose molecular basis should be evaluated as precisely as possible [ 5 ].…”

“…In addition, FAK is involved in further cell behavioral features, including apico-basal epithelial polarity, cell growth, proliferation, differentiation, and apoptosis [ 1 , 2 , 3 , 4 ]. In the context of carcinogenesis, FAK is overexpressed and highly active in many histological tumor samples as well as cancer cell lines [ 5 ]. It stimulates the downregulation of the epithelial cell adhesion molecule E-Cadherin, whose loss is a cornerstone in epithelial-mesenchymal transition (EMT) [ 6 , 7 ].…”

“…In addition, FAK supports the migratory phenotype of epithelial cells, thereby contributing to the migration and invasion of cancer cells as well as metastasis, as shown for epidermoid carcinoma and various squamous cell carcinomas [ 6 , 8 , 9 , 10 , 11 ]. Therefore, low molecular weight inhibitors of FAK activity, which prevent, e.g., its auto-phosphorylation at tyrosine residue 397 (Y397), are of high clinical interest [ 5 ].…”

The dawn of precision medicine in diffuse-type gastric cancer

“… 199 As RHOA mutations promoted the activation and dependency of focal adhesion kinase (FAK), the small molecule inhibitors of FAK, including GSK-2256098, VS-6063, CEP-37440, VS-6062, VS-4718, and BI-853520, are considered to be a promising cancer therapy in RHOA mutant GC. 200 Furthermore, FAK may also serve as a target even for DGC without RHOA mutation. 90 These preclinical findings support the clinical utility of targeting the RHOA signaling pathway.…”

Talin-drug interaction reveals a key molecular determinant for biphasic mechanical effect: studied under single-molecule resolution

“…Studies have reported integrins, microtubule and actin are currently used as potential drug targets. Similarly, focal adhesion kinase (FAK) degraders have been successfully developed through different methodologies including PROTAC technology 5,6 . At molecular level, these small molecule drugs could modulate the structural stability of these proteins, which in turn could affect their mechanical response and protein interactions.…”