A novel FAK-targeted degrader: Design, synthesis, and therapeutic potential against colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Focal adhesion kinase (FAK) is overexpressed in colorectal cancer (CRC), driving tumor progression.
• Current FAK inhibitors target kinase activity but not non-enzymatic functions.
• Existing FAK-targeting PROTACs often prioritize degradation efficiency over warhead optimization.

Purpose of the Study:

• To design and synthesize novel FAK-targeting PROTACs with optimized warhead and linker components.
• To identify a potent FAK degrader for potential CRC therapy.

Main Methods:

• Systematic design and synthesis of a series of FAK-targeting PROTACs.
• Evaluation of compound potency using IC50 values in HCT116 CRC cells.
• Assessment of cytotoxicity in normal L02 cells.
• Western blot analysis to confirm FAK protein degradation.
• Colony formation assays and HUVEC cell proliferation inhibition assays to assess anti-tumor and anti-angiogenic activity.

Main Results:

• Compound 16g emerged as the most potent FAK degrader, with an IC50 of 1.56 μM against HCT116 cells.
• 16g exhibited no cytotoxicity toward normal L02 cells.
• Western blot confirmed dose-dependent FAK protein degradation by 16g.
• 16g significantly suppressed colony formation and demonstrated anti-angiogenic activity.

Conclusions:

• Compound 16g is a novel and potent FAK degrader.
• 16g shows significant therapeutic potential for colorectal cancer treatment.
• The optimized PROTAC strategy offers a promising approach for targeting FAK in cancer therapy.