PT  - JOURNAL ARTICLE
AU  - Yang, Zhenyu
AU  - Wang, Dan
AU  - Johnson, James K.
AU  - Pascal, Laura E.
AU  - Takubo, Keita
AU  - Avula, Raghunandan
AU  - Chakka, Anish Bhaswanth
AU  - Zhou, Jianhua
AU  - Chen, Wei
AU  - Zhong, Mingming
AU  - Song, Qiong
AU  - Ding, Hui
AU  - Wu, Zeyu
AU  - Chandran, Uma R.
AU  - Maskrey, Taber S.
AU  - Nelson, Joel B.
AU  - Wipf, Peter
AU  - Wang, Zhou
TI  - A Novel Small Molecule Targets Androgen Receptor and Its Splice Variants in Castration-Resistant Prostate Cancer
AID  - 10.1158/1535-7163.MCT-19-0489
DP  - 2020 Jan 01
TA  - Molecular Cancer Therapeutics
PG  - 75--88
VI  - 19
IP  - 1
4099  - http://mct.aacrjournals.org/content/19/1/75.short
4100  - http://mct.aacrjournals.org/content/19/1/75.full
SO  - Mol Cancer Ther2020 Jan 01; 19
AB  - 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.