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Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs
- Source :
- Angewandte Chemie. 133:23515-23522
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
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.
- Subjects :
- Ubiquitin-Protein Ligases
Antineoplastic Agents
Protein degradation
Catalysis
Metastasis
Focal adhesion
Mice
Mediator
Cell Movement
In vivo
Cell Line, Tumor
medicine
Animals
Humans
Molecular Structure
biology
Chemistry
Proteolysis targeting chimera
Cancer
Dipeptides
General Chemistry
General Medicine
medicine.disease
Ubiquitin ligase
Focal Adhesion Kinase 1
Benzamides
Proteolysis
biology.protein
Cancer research
biological phenomena, cell phenomena, and immunity
Subjects
Details
- ISSN :
- 15213757 and 00448249
- Volume :
- 133
- Database :
- OpenAIRE
- Journal :
- Angewandte Chemie
- Accession number :
- edsair.doi.dedup.....78bf53bda7c0c58ce1f7c8658407374a