Cell-penetrating bisubstrate-based protein kinase C inhibitors

van Wandelen, L. T. M., van Ameijde, J., Ismail-Ali, A. F., van Ufford, H. C. (L.) Q., Vijftigschild, L. A. W., Beekman, J. M., Martin, N. I., Ruijtenbeek, R. and Liskamp, R. M. J. (2013) Cell-penetrating bisubstrate-based protein kinase C inhibitors. ACS Chemical Biology, 8(7), pp. 1479-1487. (doi:10.1021/cb300709g)

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Publisher's URL: http://dx.doi.org/10.1021/cb300709g

Abstract

Although protein kinase inhibitors present excellent pharmaceutical opportunities, lack of selectivity and associated therapeutic side effects are common. Bisubstrate-based inhibitors targeting both the high-selectivity peptide substrate binding groove and the high-affinity ATP pocket address this. However, they are typically large and polar, hampering cellular uptake. This paper describes a modular development approach for bisubstrate-based kinase inhibitors furnished with cell-penetrating moieties and demonstrates their cellular uptake and intracellular activity against protein kinase C (PKC). This enzyme family is a longstanding pharmaceutical target involved in cancer, immunological disorders, and neurodegenerative diseases. However, selectivity is particularly difficult to achieve because of homology among family members and with several related kinases, making PKC an excellent proving ground for bisubstrate-based inhibitors. Besides the pharmacological potential of the novel cell-penetrating constructs, the modular strategy described here may be used for discovering selective, cell-penetrating kinase inhibitors against any kinase and may increase adoption and therapeutic application of this promising inhibitor class.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert
Authors: van Wandelen, L. T. M., van Ameijde, J., Ismail-Ali, A. F., van Ufford, H. C. (L.) Q., Vijftigschild, L. A. W., Beekman, J. M., Martin, N. I., Ruijtenbeek, R., and Liskamp, R. M. J.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:ACS Chemical Biology
Publisher:American Chemical Society
ISSN:1554-8929
ISSN (Online):1554-8937

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