Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs

  • Angew Chem Int Ed Engl. 2021 Oct 18;60(43):23327-23334. doi: 10.1002/anie.202109237.
Robert P Law  1 ,  Joao Nunes  1 ,  Chun-Wa Chung  1 ,  Marcus Bantscheff  2 ,  Karol Buda  1 ,  Han Dai  1 ,  John P Evans  1 ,  Adam Flinders  1 ,  Diana Klimaszewska  1 ,  Antonia J Lewis  1 ,  Marcel Muelbaier  2 ,  Paul Scott-Stevens  1 ,  Peter Stacey  1 ,  Christopher J Tame  1 ,  Gillian F Watt  1 ,  Nico Zinn  2 ,  Markus A Queisser  1 ,  John D Harling  1 ,  Andrew B Benowitz  1
Affiliations
  • 1. GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
  • 2. Cellzome GmbH, a GSK company, Meyerhofstraße 1, 69117, Heidelberg, Germany.
PMID: 34416073 DOI: 10.1002/anie.202109237
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.

Keywords
cancer; drug design; medicinal chemistry; protein degradation; proteolysis-targeting chimeras (PROTACs).
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