Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 16, Pages 4372-4385Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201707875
Keywords
covalent inhibitors; cysteine; cysteinome; kinases; selectivity
Categories
Funding
- DFG [Sonderforschungsbereich SFB1177]
- AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genome Canada through Ontario Genomics Institute [1097737]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant] [1097737, 115766]
- Wellcome Trust [1097737]
- Janssen [1097737]
- Merck Co. [1097737]
- Novartis Pharma AG [1097737]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Pfizer [1097737]
- Sao Paulo Research Foundation-FAPESP [1097737]
- Sao Paulo Research Foundation-Takeda [1097737]
- Centre of Excellence Macromolecular complexes (CEF) at Frankfurt University [1097737]
- German Cancer network DKTK
Ask authors/readers for more resources
Drugs that function through covalent bond formation represent a considerable fraction of our repository of effective medicines but safety concerns and the complexity of developing covalent inhibitors has rendered covalent targeting a less attractive strategy for rational drug design. The recent approval of four covalent kinase inhibitors and the development of highly potent covalent kinase probes with exceptional selectivity has raised significant interest in industry and academic research and validated the concept of covalent kinase targeting for clinical applications. The abundance of cysteines at diverse positions in and around the kinase active site suggests that a large fraction of kinases can be targeted by covalent inhibitors. Herein, we review recent developments of this rapidly growing area in kinase drug development and highlight the unique opportunities and challenges of this strategy.
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