Hoffelner, Beate Sandra and Andreev, Stanislav and Plank, Nicole and Koch, Pierre (2023) Photocaging of Pyridinylimidazole-Based Covalent JNK3 Inhibitors Affords Spatiotemporal Control of the Binding Affinity in Live Cells. PHARMACEUTICALS, 16 (2): 264. ISSN , 1424-8247
Full text not available from this repository. (Request a copy)Abstract
The concept of photocaging represents a promising approach to acquire spatiotemporal control over molecular bioactivity. To apply this strategy to pyridinylimidazole-based covalent JNK3 inhibitors, we used acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (1) as a lead compound to design novel covalent inhibitors of JNK3 by modifying the amide bond moiety in the linker. The newly synthesized inhibitors demonstrated IC50 values in the low double-digit nanomolar range in a radiometric kinase assay. They were further characterized in a NanoBRET (TM) intracellular JNK3 assay, where covalent engagement of the target enzyme was confirmed by compound washout experiments and a loss in binding affinity for a newly generated JNK3(C154A)-NLuc mutant. The most potent compound of the series, N-(3-acrylamidophenyl)-4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)benzamide (13), was equipped with a photolabile protecting group leading to a nearly 10-fold decrease in intracellular JNK3 binding affinity, which was fully recovered by UV irradiation at a wavelength of 365 nm within 8 min. Our results highlight that photocaged covalent inhibitors can serve as a pharmacological tool to control JNK3 activity in live cells with light.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-KINASES; RELEASE; DISEASE; DESIGN; TARGET; POTENT; MODEL; kinase inhibitor; pyridinyl imidazole; covalent inhibitor; photoactivation; caging group; JNK3 |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Mar 2024 17:26 |
| Last Modified: | 09 Mar 2024 17:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59484 |
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