Abstract 2182: Novel ATP-competitive protein kinase D inhibitors: in vitro characterization and SAR analysis.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Protein Kinase Ds (PKDs) are serine/threonine kinases targeted by the second messenger diacylglycerol. The three isoforms of PKD (PKD1, PKD2, and PKD3) have emerged as key mediators in diverse cellular processes pertaining to cancer development including proliferation, apoptosis, migration/invasion and angiogenesis. Potent and selective PKD inhibitors are powerful tools in dissecting PKD-mediated cellular pathways and promising leads for developing effective anticancer agents. From targeted kinase inhibitor library screens we identified three highly potent novel ATP-competitive PKD inhibitors, IKK 16, 1-naphthyl PP1 and SD 208 with in vitro PKD inhibitory activity in low nanomolar range. All inhibitors except IKK 16 showed high selectivity for PKD relative to the related kinase family PKC and CAMK. When tested in LNCaP prostate cancer cells the compounds inhibited phorbol ester-induced PKD1 activation in a concentration dependent manner. SD 208 was found to be most specific for PKD and it did not affect the PKC mediated trans-phosphorylation of PKD1 at S744/748. Importantly, 1-naphthyl PP1 and SD 208 potently blocked prostate cancer cell proliferation and concentration-dependently induced cell death. SAR analysis of SD 208 and 1-naphthyl PP1 led to identification of key structural elements that are important for PKD inhibitory activity. In summary, we have identified and evaluated a panel of structurally divergent novel ATP-competitive PKD small molecule inhibitors with potent PKD inhibitory activities that could be further developed as potential antitumor agents in prostate cancer. Citation Format: Manuj Tandon, James Johnson, Elisa Farber, Evan Carder, Peter Wipf, Qiming J. Wang. Novel ATP-competitive protein kinase D inhibitors: in vitro characterization and SAR analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2182. doi:10.1158/1538-7445.AM2013-2182