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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
Design and analysis of the 4-anilinoquin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure-activity relationships

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.

4-anilinoquinazoline, 4-anilinoquinoline, cyclin G associated kinase, quantitative structure-activity relationships, Water Network
1860-7179
26-49
Asquith, Christopher R.M.
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Laitinen, Tuomo
b37037c5-4eac-4533-8246-5a49213bae9b
Bennett, James M.
687a7de9-d3e5-4190-b4b7-f3f3a6df8c3f
Wells, Carrow I.
b1b55315-9748-46cb-919f-663298061454
Elkins, Jonathan M.
103a8855-1ca0-4abb-9ce2-a7c4f350fe39
Zuercher, William J.
e464feb0-ea00-4c90-8fb4-2f31caba1040
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Poso, Antti
84d2fb32-9d24-4ad9-a9ca-a66e3cab8a3d
Asquith, Christopher R.M.
51f24044-1f40-43c7-806a-2e78fdcc2733
Laitinen, Tuomo
b37037c5-4eac-4533-8246-5a49213bae9b
Bennett, James M.
687a7de9-d3e5-4190-b4b7-f3f3a6df8c3f
Wells, Carrow I.
b1b55315-9748-46cb-919f-663298061454
Elkins, Jonathan M.
103a8855-1ca0-4abb-9ce2-a7c4f350fe39
Zuercher, William J.
e464feb0-ea00-4c90-8fb4-2f31caba1040
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Poso, Antti
84d2fb32-9d24-4ad9-a9ca-a66e3cab8a3d

Asquith, Christopher R.M., Laitinen, Tuomo, Bennett, James M., Wells, Carrow I., Elkins, Jonathan M., Zuercher, William J., Tizzard, Graham J. and Poso, Antti (2020) Design and analysis of the 4-anilinoquin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure-activity relationships. ChemMedChem, 15 (1), 26-49. (doi:10.1002/cmdc.201900521).

Record type: Article

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.

Text
QSAR ChemMedChem - 17thOct2019 - Accepted Manuscript
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More information

e-pub ahead of print date: 1 November 2019
Published date: 7 January 2020
Keywords: 4-anilinoquinazoline, 4-anilinoquinoline, cyclin G associated kinase, quantitative structure-activity relationships, Water Network

Identifiers

Local EPrints ID: 436887
URI: http://eprints.soton.ac.uk/id/eprint/436887
ISSN: 1860-7179
PURE UUID: 384eac04-a811-45c3-838c-41217011182e
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779

Catalogue record

Date deposited: 13 Jan 2020 17:31
Last modified: 26 Nov 2021 06:38

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Contributors

Author: Christopher R.M. Asquith
Author: Tuomo Laitinen
Author: James M. Bennett
Author: Carrow I. Wells
Author: Jonathan M. Elkins
Author: William J. Zuercher
Author: Antti Poso

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