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

Abstract

STAT3 is well corroborated preclinically as a cancer therapeutic target, but tractable translational strategies for its blockade by small molecule inhibitors have remained elusive. In this study, we report the development of a novel class of bifunctional STAT3 inhibitors, based on conjugation of a diarylidenyl-piperidone (DAP) backbone to an N-hydroxypyrroline (-NOH) group, which exhibits minimal toxicity against normal cells and good oral bioavailability. Molecular modeling studies of this class suggested direct interaction with the STAT3 DNA binding domain. In particular, the DAP compound HO-3867 selectively inhibited STAT3 phosphorylation, transcription, and DNA binding without affecting the expression of other active STATs. HO-3867 exhibited minimal toxicity toward noncancerous cells and tissues but induced apoptosis in ovarian cancer cells. Pharmacologic analysis revealed greater bioabsorption and bioavailability of the active (cytotoxic) metabolites in cancer cells compared with normal cells. The selective cytotoxicity of HO-3867 seemed to be multifaceted, eliciting differential activation of the Akt pathway in normal versus cancer cells. RNAi attenuation experiments confirmed the requirement of STAT3 for HO-3867-mediated apoptosis in ovarian cancer cells. In vivo testing showed that HO-3867 could block xenograft tumor growth without toxic side effects. Furthermore, in primary human ovarian cancer cells isolated from patient ascites, HO-3867 inhibited cell migration/invasion and survival. Our results offer preclinical proof-of-concept for HO-3867 as a selective STAT3 inhibitor to treat ovarian cancer and other solid tumors where STAT3 is widely upregulated.

• Authors: Kellie S Rath, Shan K Naidu, Pushpa Lata, Hemant K Bid, Brian K Rivera, Georgia A McCann, Brent J Tierney, Adam C Elnaggar, Veronica Bravo, Gustavo Leone, Peter Houghton, Kálmán Hideg, Periannan Kuppusamy, David E Cohn, Karuppaiyah Selvendiran
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 8 Pg. 2316-27 (Apr 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24590057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 AACR.

Chemical References

• (3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one)
• Antineoplastic Agents
• Piperidones
• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• CHO Cells
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Cricetulus
• Cytotoxicity, Immunologic
• Female
• Humans
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• Piperidones (pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction
• Transcriptional Activation
• Transfection
• Xenograft Model Antitumor Assays