期刊
CHEMMEDCHEM
卷 15, 期 1, 页码 26-49出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201900521
关键词
cyclin G associated kinase; 4-anilinoquinoline; 4-anilinoquinazoline; quantitative structure-activity relationships; Water Network
资金
- AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genome Canada [1097737]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant] [1097737, 115766]
- Janssen [1097737]
- Merck KGaA Darmstadt Germany [1097737]
- MSD [1097737]
- Novartis Pharma AG [1097737]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Pfizer [1097737]
- Sao Paulo Research Foundation-FAPESP [1097737]
- Takeda [1097737]
- Wellcome [1097737, 106169/ZZ14/Z]
- Biocenter Finland/DDCB
- EPSRC UK National Crystallography Service
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.
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