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Synthesis and evaluation of naphthalene derivatives as potent STAT3 inhibitors and agents against triple-negative breast cancer growth and metastasis

  • Preclinical study
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Abstract

Purpose

Triple-negative breast cancer (TNBC) represents the worst prognostic subtype of breast cancer and lacks targeted therapeutic drugs. Signal transducer and activator of transcription 3 (STAT3) is overexpressed and constitutively activated in TNBCs and associated with poor patient outcomes. However, no agents targeting STAT3 have been successfully developed and marketed. Selective Estrogen Receptor Modulators (SERMs) have been reported as potential inhibitors of the IL-6/STAT3 signaling pathway. Naphthalene compounds have good pharmacological activity and significant anti-cancer activity. In this study, we synthesized a new series of naphthalene derivatives with the general structure of SERM and evaluated their effects on TNBC and STAT3 signals.

Methods

A new series of compounds based on the scaffold of SERMs and an amino group were designed and screened based on the structure–activity relationship by MTT assay. The binding activity of SMY002 to STAT3 was predicted and validated by docking and SPR. The STAT3 signaling target and anti-cancer effects of SMY002 were evaluated with three TNBC cell lines and the mice transplanted tumor model.

Results

Among the compounds, SMY002 displayed the most potent activity, which could directly interact with STAT3 SH2-domain, and strongly inhibit the phosphorylation, dimerization, nuclear distribution, transcriptional activity, and target genes expression of STAT3. Furthermore, SMY002 markedly suppressed migration, invasion, survival, growth, and metastasis of TNBC cells in vitro and in vivo via down-regulating the expression of Cyclin D1 and MMP9.

Conclusions

SMY002 can significantly inhibit the growth and metastasis of TNBC cells by targeting the STAT3 signal.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Abbreviations

STAT3:

Signal transducer and activator of transcription 3

TNBC:

Triple-negative breast cancer

SERM:

Selective estrogen receptor modulator

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2:

Human epidermal growth factor receptor 2

GP130:

Glycoprotein 130 KD

JAKs:

Janus kinases

SH2:

Src homology domain 2

MMPs:

Matrix-metalloproteases

Tyr705:

Tyrosine 705

IC50:

Half-maximal inhibitory concentration

DMSO:

Dimethyl sulfoxide

SPR:

Surface plasmon resonance

MTT:

3-(4,5-Dimethylthiazol)-2,5-diphenyltetrazolium bromide

DAPI:

4,6-Diamidino-2-phenylindole

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Acknowledgements

We acknowledge the National Natural Science Foundation of China for funding the project (Nos. 81803575, 31902287) and the Henan Science and Technology Department of China for financing the project (No. G20190126005). We also thank the Department of Science and Technology, Government of Kaifeng, China, for funding the project (No. 21SSF003)), the Key R&D and promotion projects of Kaifeng (No. 2203008).

Funding

This work was supported by grants from the High-End Foreign Experts Introduction Plan of Henan Science and Technology Department (No. G20190126005), Kaifeng Science and Technology Development Plan Project (No. 21SSF003), Youth Fund of National Natural Science Foundation of China (No. 81803575).

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Authors and Affiliations

  1. Henan International Joint Lab for Anti-Cancer Drug Design Based On Biological Target and Drug Discovery, Henan Ruida Bio-Tech Medicine Co. Ltd, Kaifeng, 475000, China

    Zhengyan Yang, Hongyun Xu, Yupo Yang, Chaoqun Duan & Marvin Xuejun Xu

  2. School of Basic Medical Science, Henan University, Kaifeng, 475004, China

    Zhengyan Yang & Pai Zhang

  3. Huaihe Hospital of Henan University, Kaifeng, 475000, China

    Yang Wang

  4. Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York, 14263-0001, USA

    Kai Fu

  5. Institute of Microbial Engineering, Engineering Research Center for Applied Microbiology of Henan Province, School of Life Sciences of Henan University, Kaifeng, 475004, China

    Yonghong Shen

  6. Translational Medical Center, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471009, China

    Marvin Xuejun Xu

Authors
  1. Zhengyan Yang
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Contributions

All authors contributed to the study’s conception and design. Zhengyan Yang contributed to conceptualization and writing-original draft. Hongyun Xu contributed to investigation and validation. Yupo Yang and Chaoqun Duan contributed to the synthesis and analysis of the compounds. Pai Zhang contributed to the data curation. Yang Wang contributed to resource collection. Kai Fu contributed to methodology and formal analysis. Yonghong Shen contributed to the writing-reviewing, and editing of the manuscript. Marvin Xuejun Xu contributed to funding acquisition and project administration. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yonghong Shen or Marvin Xuejun Xu.

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Yang, Z., Xu, H., Yang, Y. et al. Synthesis and evaluation of naphthalene derivatives as potent STAT3 inhibitors and agents against triple-negative breast cancer growth and metastasis. Breast Cancer Res Treat 197, 255–267 (2023). https://doi.org/10.1007/s10549-022-06790-2

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