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. Epub 2021 Sep 17.

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).

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Benzamides / chemistry
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Dipeptides / chemistry
  • Dipeptides / pharmacokinetics
  • Dipeptides / pharmacology
  • Focal Adhesion Kinase 1 / antagonists & inhibitors*
  • Focal Adhesion Kinase 1 / metabolism
  • Humans
  • Mice
  • Molecular Structure
  • Proteolysis / drug effects*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Antineoplastic Agents
  • Benzamides
  • Dipeptides
  • Ubiquitin-Protein Ligases
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse