Abstract A253: HO-3867, a safe STAT3 inhibitor, is selectively cytotoxic to ovarian cancer.

We have developed a novel class of bi-functional compounds based on a diarylidenyl-piperidone (DAP) backbone conjugated to an N-hydroxypyrroline (-NOH; a nitroxide precursor) group which selectively inhibits STAT3 activation, translocation, and DNA binding activity, without affecting the expression of other pSTATs. This new STAT3 inhibitor offers advantages when compared to other STAT3-targeting molecules currently available, under development or undergoing preclinical trials. Most notably, these compounds exhibit minimal toxicity toward normal cells and tissues while inducing apoptosis in ovarian cancer cells, and exhibit good oral bioavailability. Results show that selective cytotoxicity of the lead compound, HO-3867, towards cancer cells is multi-faceted. AutoDock molecular modeling indicates that the DAP compounds interact with STAT3 at the DNA-binding domain. Liquid chromatography / Mass spectroscopy analysis demonstrates greater bioabsorption and bioavailability of active (cytotoxic) metabolites in cancer cells when compared to normal cells. Differential activation of the Akt pathway was demonstrated using Akt siRNA in normal versus cancer cells. Knockdown of STAT3 expression using two different shRNAs shows the requirement of STAT3 for HO-3867-mediated apoptosis. In vivo testing shows that HO-3867 inhibits xenograft tumor growth without toxic side effects. In addition, HO-3867 significantly inhibited cell survival, migration/invasion and induced cell death in primary ovarian cancer cell populations isolated from ascites of patients with recurrent and advanced ovarian cancer. This study provides evidence of a safe, targeted STAT3 inhibitor (HO-3867) with demonstrated efficacy in treating multiple ovarian cancer models. This suggests significant translational potential of these compounds for the treatment of ovarian cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A253. Citation Format: Karuppaiyah Selvendiran, Kellie S. Rath, Shan Naidu, Pushpa Latha, Bid Hemant, Georgia A. McCann, Veronica Bravo, Peter Houghton, Gustavo Leone, Kalman Hideg, Periannan Kuppusamy, David E. Cohn. HO-3867, a safe STAT3 inhibitor, is selectively cytotoxic to ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A253.