Abstract
The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains a major challenge for the treatment of advanced PCa, there is a pressing need for new anti-AR therapeutic avenues. In this study, we identified a binding site on the DNA binding domain (DBD) of the receptor and utilized virtual screening to discover a set of micromolar hits for the target. Through further exploration of the most potent hit (1), a structural analogue (6) was identified demonstrating 10-fold improved anti-AR potency. Further optimization resulted in a more potent synthetic analogue (25) with anti-AR potency comparable to a newly FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated that the developed inhibitors do interact with the intended target site. Importantly, the AR DBD inhibitors could effectively inhibit the growth of Enzalutamide-resistant cells as well as block the transcriptional activity of constitutively active AR splice variants, such as V7.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Androgen Receptor Antagonists / chemical synthesis
-
Androgen Receptor Antagonists / chemistry*
-
Androgen Receptor Antagonists / pharmacology
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacology
-
Benzamides
-
Binding Sites
-
Cell Line, Tumor
-
Cell Survival / drug effects
-
Computer Simulation
-
DNA / metabolism*
-
Databases, Chemical
-
Drug Resistance, Neoplasm
-
Humans
-
Imidazoles / chemical synthesis
-
Imidazoles / chemistry*
-
Imidazoles / pharmacology
-
Male
-
Molecular Conformation
-
Molecular Docking Simulation
-
Morpholines / chemical synthesis
-
Morpholines / chemistry*
-
Morpholines / pharmacology
-
Mutation
-
Nitriles
-
Phenylthiohydantoin / analogs & derivatives
-
Phenylthiohydantoin / pharmacology
-
Prostate-Specific Antigen / metabolism
-
Prostatic Neoplasms / drug therapy
-
Pyrvinium Compounds / chemistry
-
Pyrvinium Compounds / pharmacology
-
Rats
-
Receptors, Androgen / genetics
-
Receptors, Androgen / metabolism*
-
Structure-Activity Relationship
-
Thiazoles / chemical synthesis
-
Thiazoles / chemistry*
-
Thiazoles / pharmacology
-
Thiophenes / chemical synthesis
-
Thiophenes / chemistry
-
Thiophenes / pharmacology
-
Transcription, Genetic
Substances
-
4-(4-(4,5-dibromo-1H-imidazol-1-yl)thiazol-2-yl)morpholine
-
Androgen Receptor Antagonists
-
Antineoplastic Agents
-
Benzamides
-
Imidazoles
-
Morpholines
-
Nitriles
-
Pyrvinium Compounds
-
Receptors, Androgen
-
Thiazoles
-
Thiophenes
-
Phenylthiohydantoin
-
pyrvinium
-
DNA
-
enzalutamide
-
Prostate-Specific Antigen