British journal of cancer · 2025
Novel Skp1 inhibitor has potent preclinical efficacy against castration-resistant prostate cancer.
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Li Xin, Mamouni Kenza, Zhao Rui, Bai Lijuan, Chen Yanhua, Wu Yifei, Xie Zhong-Ru, Sautto Giuseppe A, Liu Degang, Bowen Nathan J, Danaher Alira, Li Dehong, Cook Nicholas, Grayson Skylar, Zhu Jedidiah, Coleman Ilsa M, Nelson Peter S, Bao Qichao, Zhou Jia, Osunkoya Adeboye O, Kucuk Omer, Gera Lajos, Wu Daqing
Аннотация
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.
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.