Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs
Autor: | Han Dai, Robert P. Law, John P. Evans, Gillian F. Watt, Chun-wa Chung, Markus A. Queisser, John D. Harling, Antonia J. Lewis, Marcus Bantscheff, João Osvaldo Rodrigues Nunes, Adam Flinders, Paul Scott-Stevens, Andrew B. Benowitz, Peter Stacey, Christopher J. Tame, Karol Buda, Diana Klimaszewska, Marcel Muelbaier, Nico Zinn |
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Rok vydání: | 2021 |
Předmět: |
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 |
Zdroj: | Angewandte Chemie. 133:23515-23522 |
ISSN: | 1521-3757 0044-8249 |
Popis: | 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. |
Databáze: | OpenAIRE |
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