2. Academic Validation
  3. 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

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

  • J Med Chem. 2019 May 9;62(9):4772-4778. doi: 10.1021/acs.jmedchem.9b00350.
Christopher R M Asquith 1 2,  Kaleb M Naegeli 3,  Michael P East 2,  Tuomo Laitinen 4,  Tammy M Havener 3,  Carrow I Wells 1,  Gary L Johnson 2,  David H Drewry 1,  William J Zuercher 1 5,  David C Morris 3
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
  • 2 Department of Pharmacology, School of Medicine , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
  • 3 UNC Catalyst for Rare Diseases , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
  • 4 School of Pharmacy, Faculty of Health Sciences , University of Eastern Finland , 70211 Kuopio , Finland.
  • 5 Lineberger Comprehensive Cancer Center , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
PMID: 30973735 DOI: 10.1021/acs.jmedchem.9b00350
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.

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