Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs
Robert P. Law, João Nunes, Chun‐wa Chung, Marcus Bantscheff, Karol Buda, Han Dai, John P. Evans, Adam Flinders, Diana Klimaszewska, Antonia J. Lewis, Marcel Muelbaier, Paul Scott‐Stevens, Peter Stacey, Christopher J. Tame, Gillian F. Watt, Nico Zinn, Markus A. Queisser, John D. Harling, Andrew B. Benowitz
Abstract
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.