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Status |
Public on Dec 31, 2019 |
Title |
Effect of Selective Androgen Receptor Degraders (SARDs) on Androgen Receptor (AR) Function in MR49F (LNCaP enzalutamide-resistant) Cells |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by array
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Summary |
Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand binding domain (LBD)-binding antagonists, are inactivated by common resistance -mechanisms. It is important to develop next-generation mechanistically-distinct drugs to treat castration- and drug- resistant prostate cancers. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. UT-34 inhibits the wild-type and LBD mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist, enzalutamide, and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-Protein Coupled Receptor, kinase, and nuclear receptor family members. Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug. MR49F cells (n=3-4/group) were maintained in charcoal-stripped serum containing medium for 48 hours and treated with vehicle, 0.1 nM R1881, or 10 uM of UT-34 in combination with 0.1 nM R1881. Twenty four hours after treatment, the cells were harvested, RNA was isolated and expression of genes was measured using microarray (Affymetrix Clarion S) UT-34 is a selective androgen receptor degrader that degrades and antagonizes the AR. UT-34 binds to the AF-1 domain of the AR and degrades the AR through ubiquitin proteasome pathways. The transcriptome study was performed to evaluate the ability of UT-34 to antagonize the enzalutamide-resistant AR function.
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Overall design |
MR49F cells were maintained in charcoal-stripped serum containing medium for 48 hours and treated with vehicle, 0.1 nM R1881, or 10 uM of UT-34 in combination with 0.1 nM R1881. Twenty four hours after treatment, the cells were harvested, RNA was isolated and expression of genes was measured using microarray (Affymetrix Clarion S)
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Contributor(s) |
Narayanan R |
Citation missing |
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Submission date |
Jun 20, 2019 |
Last update date |
Jan 02, 2020 |
Contact name |
Daniel Lee Johnson |
E-mail(s) |
djohn166@uthsc.edu
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Phone |
9014483743
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Organization name |
UTHSC
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Department |
Molecular Informatics Core
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Street address |
71 S Manassas
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City |
Memphis |
State/province |
Tennessee |
ZIP/Postal code |
38163 |
Country |
USA |
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Platforms (1) |
GPL23159 |
[Clariom_S_Human] Affymetrix Clariom S Assay, Human (Includes Pico Assay) |
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Samples (10)
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Relations |
BioProject |
PRJNA549970 |
Supplementary file |
Size |
Download |
File type/resource |
GSE133119_RAW.tar |
10.7 Mb |
(http)(custom) |
TAR (of CEL) |
Processed data included within Sample table |
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