jm500521n_si_001.pdf (733.7 kB)
Discovery and Optimization of 1,3,5-Trisubstituted Pyrazolines as Potent and Highly Selective Allosteric Inhibitors of Protein Kinase C‑ζ
journal contribution
posted on 2014-08-14, 00:00 authored by Mohammad Abdel-Halim, Britta Diesel, Alexandra K. Kiemer, Ashraf H. Abadi, Rolf W. Hartmann, Matthias EngelThere
is increasing evidence that the atypical protein kinase C,
PKCζ, 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 PKCζ inhibitors.
The rigid scaffold offered many sites for modification, all acting
as hot spots for improving activity, and gave rise to sharp structure–activity
relationships. Targeting of PKCζ 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 PKCζ 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 PKCζ inhibitors.