Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Focal adhesion kinase (FAK) plays a critical role in tumor progression and metastasis.
• Current clinical trials of FAK inhibitors have shown limited efficacy in cancer treatment.

Purpose of the Study:

• To design and characterize GSK215, a potent and selective Proteolysis Targeting Chimera (PROTAC) that degrades FAK.
• To evaluate the in vitro and in vivo efficacy of GSK215 as a potential cancer therapeutic strategy.

Main Methods:

• Design and synthesis of GSK215, a PROTAC molecule utilizing VHL E3 ligase binder and VS-4718 FAK inhibitor.
• X-ray crystallography to determine the structure of the FAK-GSK215-VHL ternary complex.
• In vitro pharmacological assays and in vivo studies in mice to assess FAK degradation and PK/PD profiles.

Main Results:

• GSK215 demonstrated potent and selective FAK degradation.
• X-ray crystallography elucidated the molecular mechanism of the ternary complex formation.
• In vivo studies showed rapid, prolonged FAK degradation (≈96 hours) and a significant PK/PD disconnect after a single dose.
• GSK215 exhibited differentiated in vitro pharmacology compared to the parent inhibitor VS-4718.

Conclusions:

• GSK215 represents a novel FAK-degrading PROTAC with potential therapeutic applications in oncology.
• FAK degradation offers a differentiated strategy compared to FAK inhibition for cancer treatment.
• GSK215 serves as a valuable tool for studying FAK-degradation biology in vivo.