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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.

Original publication

DOI

10.1002/cmdc.201900521

Type

Journal article

Journal

ChemMedChem

Publication Date

07/01/2020

Volume

15

Pages

26 - 49

Keywords

4-anilinoquinazoline, 4-anilinoquinoline, Water Network, cyclin G associated kinase, quantitative structure-activity relationships, Adenosine Triphosphate, Aniline Compounds, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Drug Design, Humans, Intracellular Signaling Peptides and Proteins, Kinetics, Molecular Conformation, Molecular Docking Simulation, Protein Binding, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Quantitative Structure-Activity Relationship, Quinazolines, Small Molecule Libraries