The phosphatidylinositol-3 kinase-Akt pathway is a phosphorylation cascade that plays an important role in controlling cell fate.  PH domain Leucine-rich repeat Protein Phosphatase (PHLPP) is a key regulator of cell survival pathways.  PHLPP opposes the effects of two kinases, Akt and protein kinase C, an important kinase in cell survival pathways.  Therefore, PHLPP is a potential therapeutic target in diseases where these pathways are either repressed, such as in diabetes and cardiovascular diseases, or over-activated as in cancer.  The phosphatase domain of PHLPP belongs to the PP2C family of phosphatases for which there are no general inhibitors.  Here we report the discovery of the first PHLPP inhibitors and propose a homology model of the PHLPP phosphatase domain that demonstrates predictive power for small molecule binding.  Using a combination of chemical and virtual screening methods we discovered small molecules, that specifically inhibit PHLPP and increase Akt signaling in cells.

Virtual and chemical screening leads to the discovery of small molecule inhibitors of the Akt phosphatase PHLPP

243rd National Meeting (2012)

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