Volume 15, Issue 1 p. 26-49
Full Paper

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

Dr. Christopher R. M. Asquith

Corresponding Author

Dr. Christopher R. M. Asquith

Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA

Search for more papers by this author
Dr. Tuomo Laitinen

Dr. Tuomo Laitinen

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland

Search for more papers by this author
James M. Bennett

James M. Bennett

Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ UK

Search for more papers by this author
Carrow I. Wells

Carrow I. Wells

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA

Search for more papers by this author
Dr. Jonathan M. Elkins

Dr. Jonathan M. Elkins

Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ UK

Structural Genomics Consortium, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo, 13083-886 (Brazil)

Search for more papers by this author
Dr. William J. Zuercher

Dr. William J. Zuercher

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA

Search for more papers by this author
Dr. Graham J. Tizzard

Dr. Graham J. Tizzard

UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield Campus, Southampton, SO17 1BJ UK

Search for more papers by this author
Prof. Antti Poso

Prof. Antti Poso

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland

University Hospital Tübingen, Deparment of Internal Medicine VIII, University of Tübingen, 72076 Tübingen, Germany

Search for more papers by this author
First published: 01 November 2019
Citations: 13

Graphical Abstract

Avoiding collateral damage: The 4-anilinoquinoline and 4-anilinoquinazoline scaffolds have been the focus of significant efforts in prior kinase drug discovery programs, which have led to a number of approved medicines. We have now designed and synthesized a series of 4-anilinoquin(az)olines 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 analysis and water mapping of the kinase ATP binding sites.

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.

Conflict of interest

The authors declare no conflict of interest.