2. Academic Validation
  3. Design and Analysis of the 4-Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure-Activity Relationships

Design and Analysis of the 4-Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure-Activity Relationships

  • ChemMedChem. 2020 Jan 7;15(1):26-49. doi: 10.1002/cmdc.201900521.
Christopher R M Asquith 1 2,  Tuomo Laitinen 3,  James M Bennett 4,  Carrow I Wells 2,  Jonathan M Elkins 4 5,  William J Zuercher 2 6,  Graham J Tizzard 7,  Antti Poso 3 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland.
  • 4 Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
  • 5 Structural Genomics Consortium, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo, 13083-886 (Brazil).
  • 6 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 7 UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK.
  • 8 University Hospital Tübingen, Deparment of Internal Medicine VIII, University of Tübingen, 72076, Tübingen, Germany.
PMID: 31675459 DOI: 10.1002/cmdc.201900521
Abstract

The 4-anilinoquinoline and 4-anilinoquinazoline ring systems have been the focus of significant efforts in prior kinase drug discovery programs, which have led to approved medicines. Broad kinome profiles of these compounds have now been assessed with the advent of advanced screening technologies. These ring systems, while originally designed for specific targets including epidermal growth factor receptor (EGFR), but actually display a number of potent collateral kinase targets, some of which have been associated with negative clinical outcomes. We have designed and synthesized a series of 4-anilinoquin(az)olines in order to better understand the structure-activity relationships of three main collateral kinase targets of quin(az)oline-based kinase inhibitors: cyclin G associated kinase (GAK), STE20-like serine/threonine-protein kinase (SLK) and serine/threonine-protein kinase 10 (STK10). This was achieved through a series of quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites and extensive small-molecule X-ray structural analysis.

Keywords

4-anilinoquinazoline; 4-anilinoquinoline; Water Network; cyclin G associated kinase; quantitative structure-activity relationships.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150782
    EGFR抑制剂
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