Dual-function antiandrogen/HDACi hybrids based on enzalutamide and entinostat

Ryan R G Barrett; Claire Nash; Marine Diennet; David Cotnoir-White; Christopher Doyle; Sylvie Mader; Axel A Thomson; James L Gleason

doi:10.1016/j.bmcl.2021.128441

Dual-function antiandrogen/HDACi hybrids based on enzalutamide and entinostat

Bioorg Med Chem Lett. 2022 Jan 1:55:128441. doi: 10.1016/j.bmcl.2021.128441. Epub 2021 Nov 9.

Authors

Ryan R G Barrett¹, Claire Nash², Marine Diennet³, David Cotnoir-White³, Christopher Doyle¹, Sylvie Mader⁴, Axel A Thomson², James L Gleason⁵

Affiliations

¹ Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada.
² Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
³ Institute for Research in Immunology and Cancer, Pavillon Marcelle Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montreal, QC H3T1J4, Canada.
⁴ Institute for Research in Immunology and Cancer, Pavillon Marcelle Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montreal, QC H3T1J4, Canada; Department of Biochemistry and Molecular Medicine, Pavillon Roger Gaudry, Université de Montréal, 2900 bd Edouard Montpetit, Montreal, QC H3T1J4, Canada.
⁵ Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada. Electronic address: jim.gleason@mcgill.ca.

PMID: 34767912
DOI: 10.1016/j.bmcl.2021.128441

Abstract

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.

Keywords: Antiandrogens; Histone deacetylase inhibitors; Hybrid molecules; Prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgen Antagonists / chemical synthesis
Androgen Antagonists / chemistry
Androgen Antagonists / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzamides / chemistry
Benzamides / pharmacology*
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 Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Molecular Structure
Nitriles / chemistry
Nitriles / pharmacology*
Phenylthiohydantoin / chemistry
Phenylthiohydantoin / pharmacology*
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Androgen Antagonists
Antineoplastic Agents
Benzamides
Histone Deacetylase Inhibitors
Nitriles
Pyridines
entinostat
Phenylthiohydantoin
enzalutamide
Histone Deacetylases

Grants and funding

156199/CIHR/Canada