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Regression of castration-resistant prostate cancer by a novel compound QW07 targeting androgen receptor N-terminal domain
- Source :
- Cell biology and toxicology. 36(5)
- Publication Year :
- 2019
-
Abstract
- Androgen deprivation therapy (ADT) via surgical or chemical castration frequently fails to halt lethal castration-resistant prostate cancer (CRPC), which is induced by multiple mechanisms involving constitutive androgen receptor (AR) splice variants, AR mutation, and/or de novo androgen synthesis. The AR N-terminal domain (NTD) possesses most transcriptional activity and is proposed as a potential target for CRPC drug development. We constructed a screening system targeting AR-NTD transcription activity to screening a compound library and identified a novel small molecule compound named QW07. The function evaluation and mechanism investigation of QW07 were carried out in vitro and in vivo. QW07 bound to AR-NTD directly, blocked the transactivation of AR-NTD, blocked interactions between co-regulatory proteins and androgen response elements (AREs), inhibited the expression of genes downstream of AR, and inhibited prostate cancer growth in vitro and in vivo. QW07 was demonstrated as an AR-NTD-specific antagonist with the potential to inhibit both canonical and variant-mediated AR signaling to regress the CRPC xenografts and is proposed as a lead compound for a specific antagonist targeting AR-NTD.
- Subjects :
- 0301 basic medicine
Male
congenital, hereditary, and neonatal diseases and abnormalities
Transcription, Genetic
medicine.drug_class
Health, Toxicology and Mutagenesis
Mice, Nude
urologic and male genital diseases
Toxicology
Response Elements
Androgen deprivation therapy
03 medical and health sciences
Transactivation
Prostate cancer
0302 clinical medicine
Protein Domains
In vivo
Cell Line, Tumor
medicine
Animals
Humans
Cell Proliferation
Mice, Inbred BALB C
Chemistry
Remission Induction
Antagonist
Cell Biology
medicine.disease
Androgen
In vitro
Androgen receptor
Prostatic Neoplasms, Castration-Resistant
030104 developmental biology
Receptors, Androgen
030220 oncology & carcinogenesis
Cancer research
Subjects
Details
- ISSN :
- 15736822
- Volume :
- 36
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Cell biology and toxicology
- Accession number :
- edsair.doi.dedup.....c5ba15b609f9dcaf96630d7131eb819d