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1,3-Disubstituted-1,2,4-triazin-6-ones with potent activity against androgen receptor-dependent prostate cancer cells.
Zhao, Shiting; Ali, Abdelsalam S; Liu, Xiaomin; Yu, Zhiwei; Kong, Xinyu; Zhang, Yan; Paul Savage, G; Xu, Yong; Lin, Bin; Wu, Donghai; Francis, Craig L.
Afiliação
  • Zhao S; Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, Chi
  • Ali AS; Drug Discovery Chemistry Team, CSIRO, Clayton, Victoria 3168, Australia.
  • Liu X; Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, Chi
  • Yu Z; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • Kong X; Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, Chi
  • Zhang Y; Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, Chi
  • Paul Savage G; Drug Discovery Chemistry Team, CSIRO, Clayton, Victoria 3168, Australia.
  • Xu Y; Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, Chi
  • Lin B; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • Wu D; Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, Chi
  • Francis CL; Drug Discovery Chemistry Team, CSIRO, Clayton, Victoria 3168, Australia. Electronic address: craig.francis@csiro.au.
Bioorg Med Chem ; 101: 117634, 2024 Mar 01.
Article em En | MEDLINE | ID: mdl-38359754
ABSTRACT
Synthesis and biological evaluation of a small, focused library of 1,3-disubstituted-1,2,4-triazin-6-ones for in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) and androgen-receptor independent (PC3) castration-resistant prostate cancer (CRPC) cells led to highly active compounds with in vitro IC50 values against 22Rv1 cells of <200 nM, and with apparent selectivity for this cell type over PC3 cells. From metabolic/PK evaluations of these compounds, a 3-benzyl-1-(2,4-dichlorobenzyl) derivative had superior properties and showed considerably stronger activity, by nearly an order of magnitude, against AR-dependent LNCaP and C4-2B cells compared to AR-independent DU145 cells. This lead compound decreased AR expression in a dose and time dependent manner and displayed promising therapeutic effects in a 22Rv1 CRPC xenograft mouse model. Computational target prediction and subsequent docking studies suggested three potential known prostate cancer targets p38a MAPK, TGF-ß1, and HGFR/c-Met, with the latter case of c-Met appearing stronger, owing to close structural similarity of the lead compound to known pyridazin-3-one derivatives with potent c-Met inhibitory activity. RNA-seq analysis showed dramatic reduction of AR signalling pathway and/or target genes by the lead compound, subsequently confirmed by quantitative PCR analysis. The lead compound was highly inhibitory against HGF, the c-Met ligand, which fitted well with the computational target prediction and docking studies. These results suggest that this compound could be a promising starting point for the development of an effective therapy for the treatment of CRPC.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Triazinas / Receptores Androgênicos / Neoplasias de Próstata Resistentes à Castração Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Triazinas / Receptores Androgênicos / Neoplasias de Próstata Resistentes à Castração Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2024 Tipo de documento: Article