Reynders, Martin and Chaikuad, Apirat and Berger, Benedict-Tilman and Bauer, Katharina and Koch, Pierre and Laufer, Stefan and Knapp, Stefan and Trauner, Dirk (2021) Controlling the Covalent Reactivity of a Kinase Inhibitor with Light. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 60 (37). pp. 20178-20183. ISSN 1433-7851, 1521-3773
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-KINASE; TARGET; DESIGN; covalent inhibitors; JNK3; kinase inhibitors; photopharmacology; photoswitches; photoswitchable affinity labels |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Sep 2022 07:54 |
| Last Modified: | 13 Sep 2022 07:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47879 |
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