2. Academic Validation
  3. Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs

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

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).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-132296
    99.85%, PROTAC FAK Degrader