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Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors Radaeva, Mariia; Li, Huifang; LeBlanc, Eric; Dalal, Kush; Ban, Fuqiang; Ciesielski, Fabrice; Chow, Bonny; Morin, Helene; Awrey, Shannon; Singh, Kriti; et al.

Abstract

The mutation-driven transformation of clinical anti-androgen drugs into agonists of the human androgen receptor (AR) represents a major challenge for the treatment of prostate cancer patients. To address this challenge, we have developed a novel class of inhibitors targeting the DNA-binding domain (DBD) of the receptor, which is distanced from the androgen binding site (ABS) targeted by all conventional anti-AR drugs and prone to resistant mutations. While many members of the developed 4-(4-phenylthiazol-2-yl)morpholine series of AR-DBD inhibitors demonstrated the effective suppression of wild-type AR, a few represented by 4-(4-(3-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (VPC14368) exhibited a partial agonistic effect toward the mutated T878A form of the receptor, implying their cross-interaction with the AR ABS. To study the molecular basis of the observed cross-reactivity, we co-crystallized the T878A mutated form of the AR ligand binding domain (LBD) with a bound VPC14368 molecule. Computational modelling revealed that helix 12 of AR undergoes a characteristic shift upon VPC14368 binding causing the agonistic behaviour. Based on the obtained structural data we then designed derivatives of VPC14368 to successfully eliminate the cross-reactivity towards the AR ABS, while maintaining significant anti-AR DBD potency.

Item Metadata

Title
Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors
Creator
Radaeva, Mariia; Li, Huifang; LeBlanc, Eric; Dalal, Kush; Ban, Fuqiang; Ciesielski, Fabrice; Chow, Bonny; Morin, Helene; Awrey, Shannon; Singh, Kriti; Rennie, Paul S.; Lallous, Nada; Cherkasov, Artem
Contributor
Vancouver Prostate Centre
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2022-09-07
Description
The mutation-driven transformation of clinical anti-androgen drugs into agonists of the human androgen receptor (AR) represents a major challenge for the treatment of prostate cancer patients. To address this challenge, we have developed a novel class of inhibitors targeting the DNA-binding domain (DBD) of the receptor, which is distanced from the androgen binding site (ABS) targeted by all conventional anti-AR drugs and prone to resistant mutations. While many members of the developed 4-(4-phenylthiazol-2-yl)morpholine series of AR-DBD inhibitors demonstrated the effective suppression of wild-type AR, a few represented by 4-(4-(3-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (VPC14368) exhibited a partial agonistic effect toward the mutated T878A form of the receptor, implying their cross-interaction with the AR ABS. To study the molecular basis of the observed cross-reactivity, we co-crystallized the T878A mutated form of the AR ligand binding domain (LBD) with a bound VPC14368 molecule. Computational modelling revealed that helix 12 of AR undergoes a characteristic shift upon VPC14368 binding causing the agonistic behaviour. Based on the obtained structural data we then designed derivatives of VPC14368 to successfully eliminate the cross-reactivity towards the AR ABS, while maintaining significant anti-AR DBD potency.
Subject
androgen receptor; ligand binding domain; agonism; drug design; X-ray crystallography; inhibitors
Genre
Article
Type
Text
Language
eng
Date Available
2023-07-18
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0434232
URI
http://hdl.handle.net/2429/85263
Affiliation
Medicine, Faculty of; Other UBC; Non UBC; Urologic Sciences, Department of
Citation
Radaeva, M.; Li, H.; LeBlanc, E.; Dalal, K.; Ban, F.; Ciesielski, F.; Chow, B.; Morin, H.; Awrey, S.; Singh, K.; et al. Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors. Cells 2022, 11, 2785
Publisher DOI
10.3390/cells11182785
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher; Postdoctoral; Graduate
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0