Development and Characterization of Selective FAK Inhibitors and PROTACs with In Vivo Activity.

Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in cancer models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small-molecule inhibition or degradation.

Lighting the way to tumor destruction.

Achieving tumor-specific protein loss remains a challenge in the delivery of proteolysis-targeting chimeras (PROTACs) as cancer therapeutics. As a solution, Wang et al. recently developed nanoformulated PROTACs (NAPs), a novel photoactivatable degradation approach. This innovative class of compounds harnesses near-infrared (NIR) light for precise PROTAC release and protein degradation in mouse tumors.