Identification of novel and potent PROTACs targeting FAK for non-small cell lung cancer: Design, synthesis, and...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase crucial for tumor progression, mediating survival, invasion, metastasis, and angiogenesis.
• Inhibiting FAK kinase activity alone is insufficient; both kinase and scaffolding functions must be addressed for complete signaling blockade.
• Proteolysis Targeting Chimera (PROTAC) technology offers a method to induce protein degradation, simultaneously eliminating both enzymatic and scaffolding functions.

Purpose of the Study:

• To design and synthesize novel FAK PROTACs to degrade FAK protein.
• To evaluate the efficacy of FAK PROTACs in inhibiting cancer cell proliferation, migration, and invasion.
• To assess the preliminary drug-like properties of the lead FAK PROTAC compound.

Main Methods:

• Design and synthesis of a series of FAK PROTACs.
• Biochemical assays to determine FAK affinity (IC50).
• Cell-based assays to measure FAK degradation, antiproliferative activity, and inhibition of cell migration/invasion in A549 cells.
• In vitro evaluation of plasma stability and membrane permeability.

Main Results:

• The optimal PROTAC, B5, demonstrated potent FAK affinity with an IC50 of 14.9 nM.
• PROTAC B5 achieved significant FAK degradation (86.4% at 10 nM) in A549 cells.
• PROTAC B5 exhibited potent antiproliferative activity (IC50 = 0.14 ± 0.01 μM) and inhibited cell migration and invasion.
• Preliminary in vitro studies indicated outstanding plasma stability and moderate membrane permeability for PROTAC B5.

Conclusions:

• FAK PROTAC B5 is a promising lead compound for cancer drug discovery.
• This study highlights the potential of PROTAC technology for targeting FAK's dual functions.
• Further exploration of FAK-degradation functions using PROTACs is warranted for cancer therapy development.