PT  - JOURNAL ARTICLE
AU  - Christopher R. M. Asquith
AU  - Tuomo Laitinen
AU  - James M. Bennett
AU  - Carrow I. Wells
AU  - Jonathan M. Elkins
AU  - William J. Zuercher
AU  - Graham Tizzard
AU  - Antti Poso
TI  - Design and analysis of the 4-anilino-quin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure activity relationships
AID  - 10.1101/757047
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 757047
4099  - http://biorxiv.org/content/early/2019/09/05/757047.short
4100  - http://biorxiv.org/content/early/2019/09/05/757047.full
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.