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Cited by 95Cytokine Signaling Pathways and InteractionsSynthesis and biological activityOvarian cancer diagnosis and treatment

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

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Rath, Kellie S., Naidu, Shan K., Lata, Pushpa, Bid, Hemant K., Rivera, Brian K., McCann, Georgia A., Tierney, Brent J., ElNaggar, Adam C. +7 more·2014·Cancer Research
DOI 10.1158/0008-5472.can-13-2433PMC PMC4286190

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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. Cancer Res; 74(8); 2316–27. ©2014 AACR.

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  • InS3-54 and HO-3867 specifically target the DNA-binding domain of STAT3, inhibit its binding to DNA, and block STAT3-mediated gene activation.

    “Other small-molecule inhibitors besides platinum-based compounds also have been identified, including InS3-54 and HO-3867, which specifically target the DNA-binding domain of STAT3, inhibit its binding to DNA, and block STAT3-mediated gene activation (Rath et al., 2014).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Rath et al., 2014

    In Results (‘DAPs target STAT3’; page not provided), the paper reports that HO-3867 is predicted to interact with STAT3’s DNA-binding domain, inhibits STAT3 DNA binding, and reduces a transcriptional reporter signal. The cited paper does not establish these claims for InS3-54; its experiments here concern HO-3867 and H-4073. (LLM, conf=0.90)

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Research works printed but not linked: 25

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Sorted by citations

Authors
Rath, K. S., Naidu, S. K., Lata, P., Bid, H. K., Rivera, B. K., McCann, G. A., Tierney, B. J., ElNaggar, A. C., Bravo, V., Leone, G., Houghton, P., Hideg, K., Kuppusamy, P., Cohn, D. E., & Selvendiran, K.
Affiliations
Dartmouth College (US)
Corresponding author
Selvendiran, Karuppaiyah
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2014-04-15
Volume
74
Issue
8
Pages
2316-2327
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-13-2433
PMC
PMC4286190
OpenAlex
W2012297967
Cited by
95
References
2
Citations by year
2026: 6 · 2025: 11 · 2024: 11 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 7 · 2018: 10 · 2017: 7 · 2016: 9 · 2015: 5 · 2014: 5
FWCI
4.19
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Yale University
  • National Cancer Institute (R01CA176078, P01CA097189, P30CA016058)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
Keywords
HO-3867, STAT3 inhibitor, ovarian cancer, selective cytotoxicity, apoptosis, AKT pathway, oral bioavailability, xenograft tumor growth, cell migration and invasion
MeSH terms
Animals, Antineoplastic Agents, Cricetulus, Cytotoxicity, Immunologic, Female, Humans, Ovarian Neoplasms, Piperidones, Transfection, Signal Transduction, Transcriptional Activation, CHO Cells, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Growth Processes, STAT3 Transcription Factor

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