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.
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.
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.
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.
British journal of cancer. 2025 Apr 19 [Epub ahead of print]
Xin Li, Kenza Mamouni, Rui Zhao, Lijuan Bai, Yanhua Chen, Yifei Wu, Zhong-Ru Xie, Giuseppe A Sautto, Degang Liu, Nathan J Bowen, Alira Danaher, Dehong Li, Nicholas Cook, Skylar Grayson, Jedidiah Zhu, Ilsa M Coleman, Peter S Nelson, Qichao Bao, Jia Zhou, Adeboye O Osunkoya, Omer Kucuk, Lajos Gera, Daqing Wu
Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA., Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA., School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, GA, USA., Florida Research and Innovation Center, Cleveland Clinic, Port St, Lucie, FL, USA., Sartorius Corporation, Bohemia, NY, USA., Division of Human Biology, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA., Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA., Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, School of Medicine, Aurora, CO, USA. ., Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA. .