Development of Small Molecule Activators of Protein Phosphotase 2A (SMAPs) for the Treatment of Castration Resistant Prostate Cancer
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2016
- Accession Number
- AD1022162
Entities
People
- Stephen R Plymate
Organizations
- University of Washington