Profiling crystal engineered ligands for targeting treatment resistant androgen receptors.
5 affiliations
- 1Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, WI, United States.
- 2Department of Chemistry, University of Iowa, Iowa, IA, United States.
- 3Département de Pharmacologie-physiologie, Faculté de Médecine et des Sciences de La Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.
- 4Département de Chimie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
- 5Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
Abstract
Introduction
Prostate cancer (PCa) is one of the principal contributors to health burden in the aging male population. PCa develops through dysregulation of androgen receptor (AR) signaling pathways. Despite improvements in diagnostic techniques and interventions, no pharmacological measures with long term efficacy have been established once PCa advances to castration resistant prostate cancer (CRPC). To circumvent this issue, tetra-aryl cyclobutanes (CBs) have been proposed as structurally distinct compounds with a mechanism of action differing from traditional androgen receptor pathway inhibitor (ARPI).Methods
Here, we apply principles of crystal engineering and solid state synthesis to expand the class of CBs through strategic derivatization. The synthesis of the CB occurs quantitatively, producing no side products. We demonstrate how head-to-tail stacking interactions of halo-pyrimidine rings can be exploited to stack and align unsymmetrical alkenes to undergo [2 + 2] photodimerization to generate the CB in the solid state. We examine the structure-function relationships of CBs in vitro by profiling AR mediated transcriptional activity, receptor translocation, and cell viability. Moreover, we explored putative binding interactions of ClCB and BrCB ligands across distinct AR mutants (wild-type, T877A, and F877L/T878A) using molecular docking.Results/discussion
In total, our data suggest that CBs have unexploited therapeutic potential in CRPC and that green chemistry and crystal engineering principles offer a unique route to generate these drug candidates.
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BibTeX
@article{colah2026profiling,
title = {{Profiling crystal engineered ligands for targeting treatment resistant androgen receptors.}},
author = {Avan Navaz Colah and Charles Izuchukwu Ezekiel and Sára Ferková and Pierre-Luc Boudreault and Leonard R MacGillivray and William A Ricke},
journal = {Frontiers in pharmacology},
year = {2026},
month = sep,
doi = {10.3389/fphar.2026.1813002},
url = {https://europepmc.org/article/MED/42865643},
note = {CC BY},
}
RIS
TY - JOUR
TI - Profiling crystal engineered ligands for targeting treatment resistant androgen receptors.
AU - Avan Navaz Colah
AU - Charles Izuchukwu Ezekiel
AU - Sára Ferková
AU - Pierre-Luc Boudreault
AU - Leonard R MacGillivray
AU - William A Ricke
PY - 2026
DA - 2026/09/28
JO - Frontiers in pharmacology
DO - 10.3389/fphar.2026.1813002
UR - https://europepmc.org/article/MED/42865643
AB - Introduction Prostate cancer (PCa) is one of the principal contributors to health burden in the aging male population. PCa develops through dysregulation of androgen receptor (AR) signaling pathways. Despite improvements in diagnostic techniques and interventions, no pharmacological measures with long term efficacy have been established once PCa advances to castration resistant prostate cancer (CRPC). To circumvent this issue, tetra-aryl cyclobutanes (CBs) have been proposed as structurally distinct compounds with a mechanism of action differing from traditional androgen receptor pathway inhibitor (ARPI).Methods Here, we apply principles of crystal engineering and solid state synthesis to expand the class of CBs through strategic derivatization. The synthesis of the CB occurs quantitatively, producing no side products. We demonstrate how head-to-tail stacking interactions of halo-pyrimidine rings can be exploited to stack and align unsymmetrical alkenes to undergo [2 + 2] photodimerization to generate the CB in the solid state. We examine the structure-function relationships of CBs in vitro by profiling AR mediated transcriptional activity, receptor translocation, and cell viability. Moreover, we explored putative binding interactions of ClCB and BrCB ligands across distinct AR mutants (wild-type, T877A, and F877L/T878A) using molecular docking.Results/discussion In total, our data suggest that CBs have unexploited therapeutic potential in CRPC and that green chemistry and crystal engineering principles offer a unique route to generate these drug candidates.
SN - 1663-9812
ER -