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Translational Therapeutics

Novel Skp1 inhibitor has potent preclinical efficacy against castration-resistant prostate cancer

British Journal of Cancer volume 132, pages 1188–1199 (2025)Cite this article

Subjects

Abstract

Background

Metastatic, castration-resistant prostate cancer (mCRPC) directly contributes to the mortality and morbidity of prostate cancer. It is imperative to identify new molecular targets and discover effective therapeutic agents against lethal mCRPC.

Methods

The anticancer activities and mechanism of action of the small-molecule lead compound were investigated in preclinical models of human prostate cancer. Immunohistochemistry was employed to determine the expression of S-phase kinase-associated protein 1 (Skp1) in human prostate tissues.

Results

GH501 demonstrates nanomolar potency in the NCI-60 human cancer cell panel and multiple mCRPC cell lines with diverse genetic backgrounds, including those resistant to androgen deprivation therapy drugs. Mechanistically, GH501 may bind Skp1 and disrupt the physical interaction between Skp1 and S-phase kinase-associated protein 2 (Skp2) within the Skp1-Cullin1-F-box protein ubiquitin ligase complexes (SCF), thereby affecting multiple oncogenic signals implicated in mCRPC progression, including p21, p27, β-catenin, cyclin D1, enhancer of zeste homolog 2 (EZH2), c-Myc, and survivin. GH501 exhibits excellent in vitro and in vivo safety pharmacology, and GH501 monotherapy effectively inhibits the in vivo growth of cell- and patient-derived xenografts in intraosseous and subcutaneous models. Skp1 expression is significantly increased in human prostate cancer specimens.

Conclusion

These results indicate that interrupting Skp1-Skp2 interaction is an effective approach to target mCRPC and warrant further preclinical development of GH501 as a promising therapeutic candidate.

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Fig. 1: GH501 exhibits potent in vitro cytotoxicity in human cancer cell lines.
Fig. 2: GH501 is a putative inhibitor of Skp1-Skp2 interaction.
Fig. 3: GH501 affects multiple oncogenic signals in mCRPC cells.
Fig. 4: GH501 has excellent safety profiles.
Fig. 5: GH501 monotherapy inhibits the in vivo growth of mCRPC in multiple xenograft models.
Fig. 6: Immunohistochemical analysis of Skp1 expression in a human prostate TMA.

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Data availability

RNA sequencing data are deposited in the Gene Expression Omnibus database under the accession number GSE244150. Other relevant data supporting the findings of this study are included in this article and its Supplementary Information.

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Acknowledgements

The authors are grateful to the National Cancer Institute Developmental Therapeutics Program for the NCI-60 screening. We thank Emory University Winship Cancer Institute Cancer Tissue and Pathology core for histopathological studies, and Dr. Rhea-Beth Markowitz at Georgia Cancer Center, Augusta University, for editorial assistance.

Funding

This work was supported by National Cancer Institute grants R42CA217491 and R01CA256058 (DW), R01CA266452, R21CA277368, and P50CA097186 (PSN and IMC), R50CA274336 (IMC), National Institute on Minority Health and Health Disparities grant U54MD007590 (Project 1), Department of Education Title III Program at Clark Atlanta University, Georgia Research Alliance VentureLab grant, Emory University Winship Cancer Institute-Roswell Country Club Prostate Cancer Research Award, and Augusta University-Clark Atlanta University Prostate Cancer Pilot grant (DW), the John D. Stobo, M.D. Distinguished Chair Endowment, and the Edith & Robert Zinn Chair Endowment in Drug Discovery (JZ).

Author information

Authors and Affiliations

  1. Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA

    Xin Li, Nathan J. Bowen, Alira Danaher, Dehong Li, Nicholas Cook, Skylar Grayson, Jedidiah Zhu & Daqing Wu

  2. Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Xin Li, Kenza Mamouni, Rui Zhao, Lijuan Bai, Yanhua Chen & Daqing Wu

  3. Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

    Rui Zhao

  4. Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Lijuan Bai

  5. Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Yanhua Chen

  6. School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, GA, USA

    Yifei Wu & Zhong-Ru Xie

  7. Florida Research and Innovation Center, Cleveland Clinic, Port St, Lucie, FL, USA

    Giuseppe A. Sautto

  8. Sartorius Corporation, Bohemia, NY, USA

    Degang Liu

  9. Division of Human Biology, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA

    Ilsa M. Coleman & Peter S. Nelson

  10. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA

    Qichao Bao & Jia Zhou

  11. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA

    Adeboye O. Osunkoya

  12. Department of Urology, Emory University School of Medicine, Atlanta, GA, USA

    Adeboye O. Osunkoya, Omer Kucuk & Daqing Wu

  13. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    Omer Kucuk

  14. Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, School of Medicine, Aurora, CO, USA

    Lajos Gera

  15. MetCure Therapeutics LLC, Atlanta, GA, USA

    Lajos Gera & Daqing Wu

Authors
  1. Xin Li
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  2. Kenza Mamouni
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  3. Rui Zhao
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  4. Lijuan Bai
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  5. Yanhua Chen
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  6. Yifei Wu
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  7. Zhong-Ru Xie
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  8. Giuseppe A. Sautto
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  9. Degang Liu
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  10. Nathan J. Bowen
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  11. Alira Danaher
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  12. Dehong Li
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  13. Nicholas Cook
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  14. Skylar Grayson
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  15. Jedidiah Zhu
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  16. Ilsa M. Coleman
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  17. Peter S. Nelson
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  18. Qichao Bao
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  19. Jia Zhou
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  20. Adeboye O. Osunkoya
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  21. Omer Kucuk
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  22. Lajos Gera
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  23. Daqing Wu
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Contributions

XL: Conducted investigation, performed data curation and formal analysis, and contributed to manuscript drafting and revision. KM: Conducted investigation, performed data curation and formal analysis, and contributed to manuscript drafting. RZ: Conducted investigation, performed data curation and formal analysis. LB: Conducted investigation, performed data curation and formal analysis. YC: Conducted investigation, performed data curation and formal analysis. YW: Conducted investigation, performed data curation and formal analysis, and contributed to manuscript drafting and figure preparation. ZRX: Contributed to conceptualization, supervision, project administration, methodology, investigation, formal analysis, and manuscript editing. GAS: Contributed to conceptualization, supervision, project administration, methodology, data curation and formal analysis, and manuscript drafting and revision. DLiu: Contributed to conceptualization, methodology, investigation, formal analysis, and manuscript drafting. NJB: Contributed to conceptualization, methodology, investigation, formal analysis, and manuscript editing. AD: Conducted investigation, assisted in data curation, formal analysis, and manuscript editing. DLi: Conducted investigation, assisted in data curation and formal analysis. NC: Conducted investigation, assisted in data curation and formal analysis. SG: Conducted investigation, assisted in data curation and formal analysis. JZhu: Conducted investigation, assisted in methodology and data analysis. IMC: Contributed to conceptualization, supervision, project administration, funding acquisition, data curation and formal analysis, manuscript drafting and revision. PSN: Contributed to conceptualization, supervision, project administration, funding acquisition, and manuscript editing. QB: Conducted investigation, assisted in data curation and formal analysis. JZhou: Contributed to conceptualization, supervision, project administration, funding acquisition, and manuscript preparation. AOO: Conducted investigation, data curation and formal analysis, and contributed to manuscript preparation. OK: Reviewed and provided critical feedback on the manuscript. LG: Contributed to conceptualization, investigation, supervision, project administration, data curation and formal analysis, manuscript drafting and revision. DW: Conceptualized the study, supervised the project, conducted investigation, data curation and formal analysis, provided funding support, drafted and finalized the manuscript.

Corresponding authors

Correspondence to Lajos Gera or Daqing Wu.

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Competing interests

Lajos Gera and Daqing Wu have intellectual property interests in GH501 and related compounds. Daqing Wu has ownership interests in MetCure Therapeutics LLC. Lajos Gera and Omer Kucuk provided consultation services to MetCure Therapeutics LLC. No potential conflicts of interest were disclosed by the other authors.

Ethics approval and consent to participate

The Institutional Animal Care and Use Committee (IACUC) at Augusta University approved the animal protocol (AUP# 2014-0626) used in this study. All animal procedures were subjected to National Institutes of Health guidelines.

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Li, X., Mamouni, K., Zhao, R. et al. Novel Skp1 inhibitor has potent preclinical efficacy against castration-resistant prostate cancer. Br J Cancer 132, 1188–1199 (2025). https://doi.org/10.1038/s41416-025-02993-8

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