Dual-function antiandrogen/HDACi hybrids based on enzalutamide and entinostat.
Androgen Antagonists
/ chemical synthesis
Antineoplastic Agents
/ chemical synthesis
Benzamides
/ chemistry
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Fluorescence Resonance Energy Transfer
Fluorometry
Histone Deacetylase Inhibitors
/ chemical synthesis
Histone Deacetylases
/ metabolism
Humans
Molecular Structure
Nitriles
/ chemistry
Phenylthiohydantoin
/ chemistry
Pyridines
/ chemistry
Structure-Activity Relationship
Tumor Cells, Cultured
Antiandrogens
Histone deacetylase inhibitors
Hybrid molecules
Prostate cancer
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 01 2022
01 01 2022
Historique:
received:
01
08
2021
revised:
06
10
2021
accepted:
31
10
2021
pubmed:
13
11
2021
medline:
17
2
2022
entrez:
12
11
2021
Statut:
ppublish
Résumé
The combination of androgen receptor antagonists with histone deacetylase inhibitors (HDACi) has been shown to be more effective than antiandrogens alone in halting growth of prostate cancer cell lines. Here we have designed, synthesized and assessed a series of antiandrogen/HDACi hybrids by combining structural features of enzalutamide with either SAHA or entinostat. The hybrids are demonstrated to maintain bifunctionality using a fluorometric HDAC assay and a bioluminescence resonance energy transfer (BRET) antiandrogen assay. Antiproliferative assays showed that hybrids bearing o-aminoanilide-based HDACi motifs outperformed hydroxamic acid based HDACi's. The hybrids demonstrated selectivity for epithelial cell lines vs. stromal cell lines, suggesting a potentially useful therapeutic window.
Identifiants
pubmed: 34767912
pii: S0960-894X(21)00668-5
doi: 10.1016/j.bmcl.2021.128441
pii:
doi:
Substances chimiques
Androgen Antagonists
0
Antineoplastic Agents
0
Benzamides
0
Histone Deacetylase Inhibitors
0
Nitriles
0
Pyridines
0
entinostat
1ZNY4FKK9H
Phenylthiohydantoin
2010-15-3
enzalutamide
93T0T9GKNU
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
128441Subventions
Organisme : CIHR
ID : 156199
Pays : Canada
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.