1. Design of a Cyclin G Associated Kinase (GAK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Set to Interrogate the Relationship of EGFR and GAK in Chordoma
- Author
-
Tammy M. Havener, Christopher R. M. Asquith, Gary L. Johnson, William J. Zuercher, Tuomo Laitinen, Michael P. East, David C Morris, Kaleb M. Naegeli, David H. Drewry, and Carrow I. Wells
- Subjects
musculoskeletal diseases ,Antineoplastic Agents ,Protein Serine-Threonine Kinases ,01 natural sciences ,03 medical and health sciences ,Cell Line, Tumor ,Drug Discovery ,Chordoma ,medicine ,Humans ,Epidermal growth factor receptor ,Protein Kinase Inhibitors ,Cell Proliferation ,030304 developmental biology ,Cyclin ,EGFR inhibitors ,0303 health sciences ,biology ,Chemistry ,Kinase ,HEK 293 cells ,Intracellular Signaling Peptides and Proteins ,medicine.disease ,In vitro ,0104 chemical sciences ,ErbB Receptors ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,HEK293 Cells ,Cell culture ,Drug Design ,Aminoquinolines ,Quinazolines ,Cancer research ,biology.protein ,Molecular Medicine ,Protein Binding - Abstract
We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect.
- Published
- 2019
- Full Text
- View/download PDF