RT Journal Article
SR Electronic
T1 Design and analysis of the 4-anilino-quin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure activity relationships
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 757047
DO 10.1101/757047
A1 Christopher R. M. Asquith
A1 Tuomo Laitinen
A1 James M. Bennett
A1 Carrow I. Wells
A1 Jonathan M. Elkins
A1 William J. Zuercher
A1 Graham Tizzard
A1 Antti Poso
YR 2019
UL http://biorxiv.org/content/early/2019/09/05/757047.abstract
AB The 4-anilino-quinoline and 4-anilino-quinazoline 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), 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-anilino-quin(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) through a series of quantitative structure activity relationship (QSAR) analysis and water mapping of the kinase ATP binding sites.