Discovery and Optimization of 1,3,5-Trisubstituted Pyrazolines as Potent and Highly Selective Allosteric Inhibitors of Protein Kinase C-味
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- 作者：Mohammad Abdel-Halim ; Britta Diesel ; Alexandra K. Kiemer ; Ashraf H. Abadi ; Rolf W. Hartmann ; Matthias Engel
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：August 14, 2014
- 年：2014
- 卷：57
- 期：15
- 页码：6513-6530
- 全文大小：762K
- ISSN：1520-4804
文摘
There is increasing evidence that the atypical protein kinase C, PKC味, might be a therapeutic target in pulmonary and hepatic inflammatory diseases. However, targeting the highly conserved ATP-binding pocket in the catalytic domain held little promise to achieve selective inhibition. In the present study, we introduce 1,3,5-trisubstituted pyrazolines as potent and selective allosteric PKC味 inhibitors. The rigid scaffold offered many sites for modification, all acting as hot spots for improving activity, and gave rise to sharp structure鈥揳ctivity relationships. Targeting of PKC味 in cells was confirmed by reporter gene assay, transfection assays, and Western blotting. The strongly reduced cell-free and cellular activities toward a PIF-pocket mutant of PKC味 suggested that the inhibitors most likely bound to the PIF-pocket on the kinase catalytic domain. Thus, using a rigidification strategy and by establishing and optimizing multiple molecular interactions with the binding site, we were able to significantly improve the potency of the previously reported PKC味 inhibitors.