Explorative and therapeutic targeting of protein phosphatase PP1 holoenzymes.

In recent years, protein kinases have become highly successful drug targets, mainly for the treatment of cancer. In fact, a large fraction of ongoing clinical trials involve protein kinase inhibitors. Protein phosphatases are equally powerful drug targets to interfere with protein phosphorylation. This is impressively illustrated by the PP2B inhibitors cyclosporine A and FK506, which are clinically used as potent immunosuppressants. Clearly, PP1 inhibitors also hold great promise for the treatment of various human pathologies including cancer, neurodegenerative diseases, type-2 diabetes, heart failure and viral diseases. However, highly selective, cell-permeating inhibitors of PP1 are not yet available and it is questionable whether such agents would be useful for explorative or therapeutic purposes since they would indiscriminately inhibit all PP1 holoenzymes. A more selective approach, aimed at the development of compounds that disrupt the interaction between PP1 and (subsets of) PIPs or between selected PIPs and substrates or subcellular compartments, is clearly a more promising avenue. Such disrupting agents could be used for functional studies of specific PP1 holoenzymes (chemical genetics), but also have therapeutic potential.

Keywords:Protein(de)phosphorylation, Protein phosphatase 1, Chemical genetics, Drug development

Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences