A Novel Small Molecule Targets Androgen Receptor and Its Splice Variants in Castration-Resistant Prostate Cancer.

Autor:	Yang Z; Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China.; The Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Wang D; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Johnson JK; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania., Pascal LE; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Takubo K; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania., Avula R; Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania., Chakka AB; Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania., Zhou J; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Chen W; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Zhong M; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Song Q; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Key Laboratory of Longevity and Aging-Related Diseases, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, P.R. China., Ding H; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Wu Z; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Chandran UR; Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania., Maskrey TS; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania., Nelson JB; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Wipf P; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania. wangz2@upmc.edu pwipf@pitt.edu.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Wang Z; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. wangz2@upmc.edu pwipf@pitt.edu.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2020 Jan; Vol. 19 (1), pp. 75-88. Date of Electronic Publication: 2019 Sep 25.
DOI:	10.1158/1535-7163.MCT-19-0489
Abstrakt:	Reactivation of androgen receptor (AR) appears to be the major mechanism driving the resistance of castration-resistant prostate cancer (CRPC) to second-generation antiandrogens and involves AR overexpression, AR mutation, and/or expression of AR splice variants lacking ligand-binding domain. There is a need for novel small molecules targeting AR, particularly those also targeting AR splice variants such as ARv7. A high-throughput/high-content screen was previously reported that led to the discovery of a novel lead compound, 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)-1-(4-(2,3-dimethylphenyl)piperazin-1-yl)ethan-1-one (IMTPPE), capable of inhibiting nuclear AR level and activity in CRPC cells, including those resistant to enzalutamide. A novel analogue of IMTPPE, JJ-450, has been investigated with evidence for its direct and specific inhibition of AR transcriptional activity via a pulldown assay and RNA-sequencing analysis, PSA-based luciferase, qPCR, and chromatin immunoprecipitation assays, and xenograft tumor model 22Rv1. JJ-450 blocks AR recruitment to androgen-responsive elements and suppresses AR target gene expression. JJ-450 also inhibits ARv7 transcriptional activity and its target gene expression. Importantly, JJ-450 suppresses the growth of CRPC tumor xenografts, including ARv7-expressing 22Rv1. Collectively, these findings suggest JJ-450 represents a new class of AR antagonists with therapeutic potential for CRPC, including those resistant to enzalutamide. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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