FAK inhibitors in Cancer, a patent review

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes at sites of cell adhesion to the extracellular matrix (ECM) and mediates signalling events downstream of integrin engagement of the ECM. FAK is known to regulate cell survival, proliferation and migration. Areas covered: FAK expression has also been shown to be up-regulated in many cancer types. Previous study also indicates that FAK-mediated signaling and functions are intrinsically involved in the progression of tumor aggressiveness, suggesting that FAK is a promising target for anticancer therapies. Small molecule FAK inhibitors have been developed and are being tested in clinical phase trials. Expert Opinion: These inhibitors have demonstrated to be effective by inducing tumor cell apoptosis in addition to reducing metastasis and angiogenesis. In this review, we give updates on the design, synthesis and structure-activity relationship analysis of small molecule FAK inhibitors discovered from 2015 until now. We also review the FAK inhibitors that are in clinical development and highlight the future prospects.

Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases

“…The recognised ability of cancerrelevant, MET-independent signalling routes to activate FAKs make this kinase family, or druggable targets downstream of it, potentially more attractive therapeutic targets than MET for use in combination with CDK4/6-inhibition. FAK family kinases are a recognised drug target in cancer and inhibitors targeted to the ATP-binding pocket of their kinase domain have entered clinical trials, albeit, with limited single-agent efficacy in patients thus far [47][48][49]. Our results suggest opportunity for use of FAK inhibitors in conjunction with CDK4/6is as a potentially powerful approach to improve the outcome for patients treated with CDK4/6targeted therapies or to expand the current, approved indications through mechanismbased targeted combinations.…”

Radioiodination and biological distribution of a new s‐triazine derivative for tumor uptake evaluation

“…It acts as an intracellular mediator for extracellular events such as matrix remodeling, growth factors, and nutrient availability. FAK plays an important role in regulating cellular adhesion, motility proliferation, and survival . It also plays an important role in cancer cells survival, invasion, angiogenesis, and metastasis .…”

“…It also plays an important role in cancer cells survival, invasion, angiogenesis, and metastasis . FAK is overly expressed in ovarian, breast, pancreatic, and colorectal cancer …”

“…FAK plays an important role in regulating cellular adhesion, motility proliferation, and survival. 31 It also plays an important role in cancer cells survival, invasion, angiogenesis, and metastasis. 32 FAK is overly expressed in ovarian, breast, pancreatic, and colorectal cancer.…”

“…32 FAK is overly expressed in ovarian, breast, pancreatic, and colorectal cancer. 31,33 Based on the previous predicted target, a docking study was performed to confirm the affinity of compound 1 and 2 to the predicted target computationally. The docking study was done using the X-ray crystal structure of FAK catalytic domain (Protein Data Bank [PDB]: 4K9Y).…”