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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Focal adhesion kinase (FAK) is overexpressed in cancer and crucial for cellular processes.
• Current FAK inhibitors targeting kinase activity have shown limited clinical efficacy as single agents.
• Targeting FAK offers a promising therapeutic strategy for cancer treatment.

Purpose of the Study:

• To develop and characterize novel chemical tools for FAK inhibition and degradation.
• To evaluate the comparative efficacy of FAK inhibition versus FAK degradation in cancer models.
• To dissect the downstream signaling consequences of abolishing FAK activity.

Main Methods:

• Structure-guided design of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146).
• Assessment of FAK degradation potency, specificity, and durability in cancer cells and in vivo.
• Analysis of downstream signaling pathways and cellular phenotypes (viability, migration) in response to FAK modulation.

Main Results:

• BSJ-04-146 achieved rapid, potent, and specific FAK degradation in cancer cells with durable effects in mice.
• FAK degradation demonstrated superior efficacy compared to kinase inhibition in modulating downstream signaling.
• Targeted FAK degradation significantly improved outcomes in cancer cell viability and migration assays.

Conclusions:

• Targeted protein degradation of FAK offers advantages over traditional kinase inhibition for cancer therapy.
• BSJ-04-175 and BSJ-04-146 serve as valuable chemical probes for investigating FAK biology.
• These findings support further development of FAK degraders as a novel therapeutic approach for cancer.