Rational drug design for androgen receptor and glucocorticoids receptor dual antagonist.
Androgen Receptor Antagonists
/ metabolism
Cell Proliferation
/ drug effects
Drug Design
Humans
Male
Molecular Docking Simulation
Prostatic Neoplasms
/ drug therapy
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Protein Conformation
RNA, Messenger
/ genetics
Receptors, Androgen
/ chemistry
Receptors, Glucocorticoid
/ antagonists & inhibitors
Transcription, Genetic
/ drug effects
User-Computer Interface
Androgen receptor
Antagonist
Enzalutamide resistance
Glucocorticoids receptor
Prostate cancer
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
15 Mar 2019
15 Mar 2019
Historique:
received:
09
10
2018
revised:
15
01
2019
accepted:
15
01
2019
pubmed:
4
2
2019
medline:
27
3
2019
entrez:
4
2
2019
Statut:
ppublish
Résumé
Prostate cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male cancer mortality in the western countries. The second-generation antiandrogen enzalutamide (ENZa) can prolong survival time for patients with mCRPC. However, the overexpression of glucocorticoids receptor (GR) in mCRPC cells causes the resistance of antiandrogen and leads to the failure of androgen receptor (AR) targeting therapy. Herein, based on the chemical structures of antiandrogen and crystal structure of GR, we set up to develop GR/AR (GR and AR) dual antagonist by virtual screening and biological evaluation. We identified Z19 as a dual AR/GR antagonist. Z19 inhibited the transcription activity of both AR and GR, reducing both protein and mRNA level of the downstream proteins of GR and AR signaling, and provided a potential lead compound for the development of novel treatment agents of prostate cancer. Our work demonstrates that rational drug design is an efficient strategy in development of the GR/AR dual antagonist for the treatment of prostate cancer.
Identifiants
pubmed: 30711833
pii: S0223-5234(19)30046-7
doi: 10.1016/j.ejmech.2019.01.036
pii:
doi:
Substances chimiques
Androgen Receptor Antagonists
0
RNA, Messenger
0
Receptors, Androgen
0
Receptors, Glucocorticoid
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
232-242Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.