title: 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.affiliation: Authors' Affiliations: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center; Center for Childhood Cancer, Nationwide Children's Hospital; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center; EPR Imaging Center, Geisel School of Medicine, Dartmouth, New Hampshire; and Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Kellie S
authors.initials: KS
authors.lastname: Rath
authors.forename: Shan K
authors.initials: SK
authors.lastname: Naidu
authors.forename: Pushpa
authors.initials: P
authors.lastname: Lata
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Bid
authors.forename: Brian K
authors.initials: BK
authors.lastname: Rivera
authors.forename: Georgia A
authors.initials: GA
authors.lastname: McCann
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Tierney
authors.forename: Adam C
authors.initials: AC
authors.lastname: Elnaggar
authors.forename: Veronica
authors.initials: V
authors.lastname: Bravo
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.forename: David E
authors.initials: DE
authors.lastname: Cohn
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003412:Cricetulus; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010881:Piperidones / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C541427:(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); D000970:Antineoplastic Agents; D010881:Piperidones; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human