Abstract 3540: Characterization of a novel class of P70S6K in preclinical models

P70S6K is a serine/threonine protein kinase responsible for the phosphorylation/ regulation of several important targets like S6, BAD, and IRS1/2. It acts downstream of the mammalian target of Rapamycin (mTOR) and regulates cell growth, proliferation, survival and migration via control of protein translation and a number of important downstream effectors. The over-expression of P70S6K confers clinical aggressiveness in solid tumors, and several findings using indirect inhibition (mTOR inhibitors) or biological tools (RNAi) suggest a critical role for p70S6K signaling in the regulation of invasion and cell motility, making selective inhibitors of this kinase potential anti-metastatic agents. A novel class of phthalazine derivatives were developed that are potent and selective inhibitors of P70S6K, with IC50s for P70S6K in the low nM to sub μμ ρανγε. We have used these inhibitors to further demonstrate and confirm the usefulness of this target for the treatment of metastatic cancers. The effect of the P70S6K inhibitors in regulating cell invasion and motility were determined in several breast (MDA-MB-231, MDA-MB-468), prostate (DU-145, PC-3, and RWPE-2), and melanoma (A-375) cancer cell lines using the modified Boyden chamber assay. All the compounds tested showed dose-dependent inhibitory activity against tumor cell motility and invasion. The activity of these compounds is broad against all the cancer cell lines tested. The activity of our p70S6K inhibitors is comparable to Rapamycin and MEK inhibitors (PD325901), supporting the hypothesis that p70S6K may be a key component for both pathways. Besides the potent in vitro activity, our Lead compound was also effective in the systematic B16-F10 murine melanoma tumor model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3540. doi:10.1158/1538-7445.AM2011-3540