A Novel Small Molecule Targets Androgen Receptor and Its Splice Variants in Castration-Resistant Prostate Cancer
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2020
- Source ID
- 10.1158/1535-7163.mct-19-0489
Entities
People
- Anish Bhaswanth Chakka
- Dan Wang
- Hui Ding
- James K Johnson
- Jianhua Zhou
- Joel B. Nelson
- Keita Takubo
- Laura E Pascal
- Mingming Zhong
- Peter Wipf
- Qiong Song
- Raghunandan Avula
- Taber S. Maskrey
- Uma R. Chandran
- Wei Chen
- Zeyu Wu
- Zhenyu Yang
- Zhou Wang
Organizations
- Central South University
- Guangxi Medical University
- National Cancer Institute
- National Institutes of Health
- Sun Yat-sen University
- United States Department of Defense
- University of Pittsburgh
- University of Pittsburgh School of Medicine