3 years ago

Small molecule activators of protein phosphatase 2A for the treatment of castration-resistant prostate cancer.

Shen Yao, David Callejas, Alice C Levine, Danica Wiredja, Nilesh Zaware, Divya Hoon, Rita A Avelar, Janna Kiselar, Michael Ohlmeyer, John P Sfakianos, Steve Plymate, Cynthia Ct Sprenger, Sudeh Izadmehr, Kimberly McClinch, Goutham Narla, Daniel McQuaid, Analisa DiFeo, William K Oh, David L Brautigan, Jaya Sangodkar, Rosalie C Sears, Alexander Kirschenbaum, Daniela Schlatzer, Abbey Perl, Yiannis A Ioannou, Yixuan Gong, Maxwell Cooper, David B Kastrinsky, Matthew D Galsky, Agnes Stachnik
Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that is more difficult to treat nearly always occurs due to aberrant re-activation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth inhibitory effects of re-engineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable to enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.

Publisher URL: http://doi.org/10.1158/0008-5472.CAN-17-0123

DOI: 10.1158/0008-5472.CAN-17-0123

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