7PI4

FAK Protac GSK215 in complex with FAK and pVHL:ElonginC:ElonginB

This is a non-PDB format compatible entry.

Summary for 7PI4

• Entry DOI: 10.2210/pdb7pi4/pdb
• Descriptor: von Hippel-Lindau disease tumor suppressor, Elongin-B, Isoform 2 of Elongin-C, ... (9 entities in total)
• Functional Keywords: transferase, protac
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 74404.45

Authors

Chung, C. (deposition date: 2021-08-19, release date: 2021-09-29, Last modification date: 2024-01-31)

Primary citation

Law, R.P.,Nunes, J.,Chung, C.W.,Bantscheff, M.,Buda, K.,Dai, H.,Evans, J.P.,Flinders, A.,Klimaszewska, D.,Lewis, A.J.,Muelbaier, M.,Scott-Stevens, P.,Stacey, P.,Tame, C.J.,Watt, G.F.,Zinn, N.,Queisser, M.A.,Harling, J.D.,Benowitz, A.B.
Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs.
Angew.Chem.Int.Ed.Engl., 60:23327-23334, 2021

PubMed 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.

PubMed: 34416073
DOI: 10.1002/anie.202109237

Experimental method

X-RAY DIFFRACTION (2.24 Å)