Development of Small Molecule Activators of Protein Phosphotase 2A (SMAPs) for the Treatment of Castration Resistant Prostate Cancer
Technical Report,30 Sep 2015,29 Sep 2016
University of Washington Seattle United States
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Protein phosphatase 2A PP2A is among the most abundant serine threonine phosphatases in mammalian cells, a bona fide tumor suppressor, and a key negative regulator of critical oncogenic proteins including the androgen receptor AR, Akt, Erk, and Myc. We have recently developed a series of small molecules that activate PP2A and thereby exert anticancer effects in cell culture and xenograft models. This proposal focuses on a third generation, orally bioavailable small molecule activator of PP2A SMAP, DT-061, with improved potency and pharmaceutic properties compared to our earlier series. Activation of PP2A represents a highly novel approach to cancer treatment that may coordinately down regulate the AR and other key PP2A regulated oncogenic pathways. Purpose We hypothesize that our novel derivative DT-061 activates PP2A, down regulates key PP2A substrates, and confers anti-prostate cancer activity. The objectives of this proposal are to further probe the mechanism and activity of DT-061 in anticipation of advancing this novel approach to cancer treatment into the clinic. Scope of Research Determine the effects of DT-061 on clinically relevant patient-derived xenograft models of prostate cancer, representing various disease states and resistance mechanisms. These models will be utilized to determine the effects of DT-061 on tumor growth and the pharmacodynamic effects of treatment.
- Medicine and Medical Research