Abstract 4360: Validation of phosphodiesterase 10A as a cancer target

Abstract

Abstract Phosphodiesterase 10A (PDE10) is a cAMP and cGMP degrading PDE isozyme that is highly expressed in the brain striatum where it plays an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, likely because of low expression levels in peripheral tissues. We recently reported high levels of PDE10 in tumors and that genetic silencing by siRNA inhibits tumor cell growth with a high degree of selectivity over normal cells (Li et al., Oncogene 2014). These observations suggest that PDE10 may have an unrecognized role in tumorigenesis and represents a novel cancer target. To further test this possibility, we studied the effects of a highly specific PDE10 inhibitor, Pf-2545920 (MP-10) on colon tumor cell growth. Here we show that Pf-2545920 selectively inhibits tumor cell growth, causes G1 cell cycle arrest, and induces apoptosis. The concentration range by which Pf-2545920 inhibits tumor cell growth parallels the concentration range required to increase intracellular cyclic nucleotide levels and activate PKA and PKG. Moreover, PDE10 knockdown by siRNA reduces the sensitivity of tumor cells to the growth inhibitory activity of Pf-2545920. Using the crystal structure of PDE10 to design novel inhibitors, a series of compounds were synthesized and screened for tumor cell growth inhibitory activity and PDE10 isozyme specificity. A lead compound, ADT-030 was found to inhibit tumor cell growth and PDE10 enzymatic activity with IC50 values in the nanomolar range, but did not significantly affect the growth of normal cells. Unlike Pf-2545920, ADT-030 exhibits high selectivity for activating PKG signaling without affecting PKA signaling. Inhibitors of PKA and PKG were used to confirm that the tumor cell growth inhibitory activity associated with PDE10 inhibition involves PKG activation, while PKA activation appears to be ancillary. These findings serve to validate PDE10 as a cancer target, whereby novel inhibitors can be designed to specifically activate cGMP/PKG signaling with a high degree of tumor cell selectivity. Supported by NIH grants 1R01CA155638 and 1R01CA131378 (Piazza). Citation Format: Kevin Lee, Nan Li, Xi Chen, Bing Zhu, Larry Yet, Luciana Madeira da Silva, Suzanne Russo, Adam B. Keeton, Michael R. Boyd, Gary A. Piazza. Validation of phosphodiesterase 10A as a cancer target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4360. doi:10.1158/1538-7445.AM2015-4360