2. Academic Validation
  3. Optimization of the 4-anilinoquin(az)oline scaffold as epidermal growth factor receptor (EGFR) inhibitors for chordoma utilizing a toxicology profiling assay platform

Optimization of the 4-anilinoquin(az)oline scaffold as epidermal growth factor receptor (EGFR) inhibitors for chordoma utilizing a toxicology profiling assay platform

  • Sci Rep. 2022 Jul 27;12(1):12820. doi: 10.1038/s41598-022-15552-5.
Andrew A Bieberich 1,  Tuomo Laitinen 2,  Kaitlyn Maffuid 3,  Raymond O Fatig 3rd 1,  Chad D Torrice 3,  David C Morris 4,  Daniel J Crona 3 5,  Christopher R M Asquith 6 7 8
Affiliations

Affiliations

  • 1 AsedaSciences Inc., 1281 Win Hentschel Boulevard, West Lafayette, IN, 47906, USA.
  • 2 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland.
  • 3 Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 4 UNC Catalyst for Rare Diseases, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 5 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 6 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland. christopher.asquith@uef.fi.
  • 7 Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. christopher.asquith@uef.fi.
  • 8 Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. christopher.asquith@uef.fi.
PMID: 35896603 DOI: 10.1038/s41598-022-15552-5
Abstract

The 4-anilinoquin(az)oline is a well-known kinase inhibitor scaffold incorporated in clinical inhibitors including gefitinib, erlotinib, afatinib, and lapatinib, all of which have previously demonstrated activity against chordoma cell lines in vitro. We screened a focused array of compounds based on the 4-anilinoquin(az)oline scaffold against both U-CH1 and the epidermal growth factor receptor (EGFR) inhibitor resistant U-CH2. To prioritize the hit compounds for further development, we screened the compound set in a multiparameter cell health toxicity assay. The de-risked compounds were then screened against a wider panel of patient derived cell lines and demonstrated low micromolar efficacy in cells. We also investigated the properties that gave rise to the toxophore markers, including the structural and electronic features, while optimizing for EGFR in-cell target engagement. These de-risked leads present a potential new therapeutic avenue for treatment of chordomas and new chemical tools and probe compound 45 (UNC-CA359) to interrogate EGFR mediated disease phenotypes.

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