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New Insights on Fak and Fak Inhibitors
1Department of Pharmacy, University of Genova, Viale Benedetto XV, 3-I16132 Genova, Italy.
Background:
Focal adhesion kinase (Fak) is a cytoplasmic protein tyrosine kinase overexpressed and activated in different solid cancers; it has shown an important role in metastasis formation, cell migration, invasion and angiogenesis and consequently it has been proposed as a potential target in cancer therapy, particularly in a metastatic phase. In recent years, different investigations have highlighted the importance of new Fak inhibitors as potential anti-cancer drugs, but other studies evidenced its role in different pathologies related to the cardiac function or viral infection.
Methods:
An extensive bibliographic research (104 references) has been done concerning the structure of Fak, its importance in tumor development, but also in other pathologies currently under study. The compounds currently subjected to clinical studies were therefore treated using the appropriate databases. Finally, the main chemical scaffolds currently under preclinical investigation were analyzed, focusing on their molecular structures and on the activity structure relationships (SAR).
Results:
At the moment, only a few reversible ATP-competitive inhibitors are under investigation in pre-clinical studies and clinical trials. Other compounds, with different chemical scaffolds, are investigated to obtain more active and selective Fak inhibitors. This mini-review is a summary of different Fak functions in cancer and other pathologies; the compounds today in clinical trials and the recent chemical scaffolds (also included in patents) giving the most interesting results are investigated. In addition, PROTAC molecules are reported.
Conclusion:
All reported results evidenced that additional studies are necessary to design and synthesize new selective and more active compounds, although promising information has been obtained from associations between Fak inhibitors and other different anti- cancer drugs. In addition, the other important roles evidenced, both at the nuclear level and in non-cancerous cells, make this protein an increasingly important target in pharmaceutical chemistry.
Insights
Focal adhesion kinase (Fak) inhibitors show promise as anti-cancer drugs, particularly for metastatic cancers. Further research is needed to develop more selective and potent Fak inhibitors for various diseases.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Focal adhesion kinase (Fak) is a protein tyrosine kinase implicated in cancer progression, including metastasis, migration, invasion, and angiogenesis.
- Fak's role extends beyond cancer, with implications in cardiac function and viral infections.
- Its overexpression and activation in solid tumors position Fak as a significant therapeutic target, especially in advanced cancer stages.
Purpose of the Study:
- To review the structure and functions of Fak in cancer and other pathologies.
- To analyze Fak inhibitors currently in clinical trials and preclinical development.
- To explore novel chemical scaffolds and structure-activity relationships (SAR) for Fak inhibition.
Main Methods:
- Conducted an extensive literature review of 104 references focusing on Fak.
- Analyzed compounds in clinical studies using relevant databases.
- Examined preclinical chemical scaffolds, their molecular structures, and SAR.
Main Results:
- Currently, few reversible ATP-competitive Fak inhibitors are in preclinical or clinical investigation.
- Ongoing research focuses on developing novel chemical scaffolds for more active and selective Fak inhibitors.
- PROTAC molecules and promising patented scaffolds are also under investigation.
Conclusions:
- Additional research is essential for designing novel, selective, and potent Fak inhibitors.
- Combining Fak inhibitors with other anti-cancer drugs shows promise.
- Fak's diverse roles, including nuclear functions and involvement in non-cancerous cells, highlight its growing importance as a pharmaceutical target.
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