期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 37, 页码 20178-20183出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202103767
关键词
covalent inhibitors; JNK3; kinase inhibitors; photopharmacology; photoswitches; photoswitchable affinity labels
资金
- German Research Foundation (DFG) [SFB749]
- NIH [OD016343]
- German cancer network DKTK
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA)
- Janssen
- Merck KGaA Darmstadt Germany
- MSD
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
Covalent kinase inhibitors have shown success in recent clinical trials, with a strategy to control the reactivity of electrophiles using light to increase tissue selectivity. Researchers have developed covalent inhibitors for the kinase JNK3, which become effective inhibitors after exposure to light, supported by X-ray structures.
Covalent kinase inhibitors account for some of the most successful drugs that have recently entered the clinic and many others are in preclinical development. A common strategy is to target cysteines in the vicinity of the ATP binding site using an acrylamide electrophile. To increase the tissue selectivity of kinase inhibitors, it could be advantageous to control the reactivity of these electrophiles with light. Here, we introduce covalent inhibitors of the kinase JNK3 that function as photoswitchable affinity labels (PALs). Our lead compounds contain a diazocine photoswitch, are poor non-covalent inhibitors in the dark, and become effective covalent inhibitors after irradiation with visible light. Our proposed mode of action is supported by X-ray structures that explain why these compounds are unreactive in the dark and undergo proximity-based covalent attachment following exposure to light.
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