Profiling crystal engineered ligands for targeting treatment resistant androgen receptors

Avan Navaz Colah; Charles Izuchukwu Ezekiel; Sára Ferková; Pierre-Luc Boudreault; Leonard R MacGillivray; William A Ricke

doi:10.3389/fphar.2026.1813002

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Profiling crystal engineered ligands for targeting treatment resistant androgen receptors

Journal article

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Profiling crystal engineered ligands for targeting treatment resistant androgen receptors

Avan Navaz Colah, Charles Izuchukwu Ezekiel, Sára Ferková, Pierre-Luc Boudreault, Leonard R MacGillivray and William A Ricke

Frontiers in pharmacology, Vol.17, 1813002

09/27/2026

DOI: 10.3389/fphar.2026.1813002

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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.

androgen receptor point mutation

castration resistant prostate cancer

crystal engineering

molecular docking

solid state synthesis

Details

Title: Subtitle: Profiling crystal engineered ligands for targeting treatment resistant androgen receptors
Creators: Avan Navaz Colah - University of Wisconsin–Madison
Charles Izuchukwu Ezekiel - University of Iowa
Sára Ferková - Université de Sherbrooke
Pierre-Luc Boudreault - Université de Sherbrooke
Leonard R MacGillivray - Université de Sherbrooke
William A Ricke - University of Wisconsin–Madison
Resource Type: Journal article
Publication Details: Frontiers in pharmacology, Vol.17, 1813002
DOI: 10.3389/fphar.2026.1813002
ISSN: 1663-9812
eISSN: 1663-9812
Publisher: Frontiers Media SA.
Grant note: NIH: U54 DK104310, R01 DK131175, R01 DK127081 National Science Foundation: NSF DMR-2221086 Canada Excellence Research Chairs (CERC) Program
The author(s) declared that financial support was received for this work and/or its publication. This work was funded by NIH Grant U54 DK104310 (WAR), R01 DK131175 (WAR), and R01 DK127081 (WAR). CIE and LRM thank the National Science Foundation (NSF DMR-2221086) and the Canada Excellence Research Chairs (CERC) Program for funding.
Language: English
Date published: 09/27/2026
Academic Unit: Chemistry
Record Identifier: 9985240902402771

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