New Insights on Fak and Fak Inhibitors

Abstract

Background: Focal adhesion kinase (Fak) is a cytoplasmic protein tyrosine kinase overexpressed and activated in different solid cancer; it showed 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 highlight the importance of new Fak inhibitors as potential anti-cancer drugs, but other studies evidenced its role in different pathologies related to 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 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 inihibitors. 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 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 informations have been obtained from associations between Fak inhibitors and other different anti-cancer drugs. In addition, the other important roles evidenced, both at nuclear level and in non-cancerous cells, make this protein an increasingly important target in pharmaceutical chemistry.

The Development of BTK Inhibitors: A Five-Year Update

“…Spebrutinib shares a common diphenylaminopyrimidine (DPPY) pharmacophore with several tyrosine kinase inhibitors, such as Alk [ 31 ], focal adhesion kinase (FAK) [ 32 ], and EGFR inhibitors [ 33 , 34 ]. It is under study in combination with FAK inhibitors to treat solid tumors (particularly esophageal cancer) [ 35 ].…”

“…As previously reported, the diphenylaminopyrimidine core has been deeply investigated as a chemical scaffold that is useful in the synthesis of most kinase inhibitors [ 31 , 32 , 33 , 34 ]. Currently, Spebrutinib is the most promising compound of these analogues.…”

“…1,3,5-triazines represent an interesting scaffold for different kinase inhibitors, including BTK and FAK inhibitors [ 32 ].…”

Focal adhesion kinase inhibitors, a heavy punch to cancer

“…It has been demonstrated that FAK contains multiple functional phosphorylation sites (Tyr397, Tyr407, Tyr576, Tyr577, Tyr861, Tyr925), of which Tyr397 is one of the most important phosphorylation site [ 9 ] and interacts directly with the Src family. Tyr576 and 577 are in the activation loop of the kinase domain, which are the main sites can be phosphorylated by Src family [ 9 ]. Tyr925 is phosphorylated and binds to the junction protein Grb2 to make FAK aggregate with integrins, while Tyr397 and Tyr 861 both could recruit other SH2 proteins [ 10 ].…”

“…Over the past decades, multiple preclinical and clinical-stage FAK inhibitors have been assessed for their effects in treating cancer diseases [ 9 , 15 , 32 , 33 ]. Table 1 summarized five oral ATP-competitive FAK inhibitors that have been evaluated in clinical trials.…”