Potent and Highly Selective Allosteric Inhibitors of PKC-zeta for the Treatment of Inflammatory Diseases and Cancer
Protein kinase C zeta (PKCζ) is implicated in the development of several inflammatory diseases and a promising therapeutic target. PKCζ controls TH2 response and is important for the regulation of NF-κB transcriptional activity. Moreover, there is increasing evidence for an involvement of PKCζ in tumor development, where it controls chemoresistance and cancer–related inflammation.
Scientists of Saarland University and German University in Cairo have discovered 1,3,5-trisubstituted and 1,3,4,5-tetrasubstituted pyrazolines as a potent and selective class of allosteric PKCζ inhibitors. Several of the compounds show inhibitory activity in the nanomolar range. The compounds have an allosteric mode of action by binding the less conserved PIF pocked domain and are highly selective for the specific PKC isoform.
The present technology opens up an innovative therapeutic approach for the treatment of inflammatory diseases in which the identified compounds can serve as starting points for drug development. First experiments indicate relevance particularly for chronic obstructive pulmonary disease (COPD).
- Innovative potent small molecules for selective PKCζ inhibition
- Allosteric mode of action increases selectivity
- Highly versatile scaffold for the independent optimization of four substituents
- Specific targeting may contribute to fewer side effects
- Potential treatment of diseases with high unmet medical need