Dataset Information

Hits Discovery on the Androgen Receptor: In Silico Approaches to Identify Agonist Compounds.

ABSTRACT: The androgen receptor (AR) is a transcription factor that plays a key role in sexual phenotype and neuromuscular development. AR can be modulated by exogenous compounds such as pharmaceuticals or chemicals present in the environment, and particularly by AR agonist compounds that mimic the action of endogenous agonist ligands and whether restore or alter the AR endocrine system functions. The activation of AR must be correctly balanced and identifying potent AR agonist compounds is of high interest to both propose treatments for certain diseases, or to predict the risk related to agonist chemicals exposure. The development of in silico approaches and the publication of structural, affinity and activity data provide a good framework to develop rational AR hits prediction models. Herein, we present a docking and a pharmacophore modeling strategy to help identifying AR agonist compounds. All models were trained on the NR-DBIND that provides high quality binding data on AR and tested on AR-agonist activity assays from the Tox21 initiative. Both methods display high performance on the NR-DBIND set and could serve as starting point for biologists and toxicologists. Yet, the pharmacophore models still need data feeding to be used as large scope undesired effect prediction models.

SUBMITTER: Reau M

PROVIDER: S-EPMC6912550 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Hits Discovery on the Androgen Receptor: In Silico Approaches to Identify Agonist Compounds.

Réau Manon M Lagarde Nathalie N Zagury Jean-François JF Montes Matthieu M

Cells 20191113 11

The androgen receptor (AR) is a transcription factor that plays a key role in sexual phenotype and neuromuscular development. AR can be modulated by exogenous compounds such as pharmaceuticals or chemicals present in the environment, and particularly by AR agonist compounds that mimic the action of endogenous agonist ligands and whether restore or alter the AR endocrine system functions. The activation of AR must be correctly balanced and identifying potent AR agonist compounds is of high intere ...[more]

PMID: 31766271

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Project description:BackgroundThe benefit of inducing cellular senescence as a tumor suppressive strategy remains questionable due to the senescence-associated secretory phenotype. Hence, studies and development of senolytic compounds that induce cell death in senescent cells have recently emerged. Senescent cells are hypothesized to exhibit different upregulated pro-survival/anti-apoptotic networks depending on the senescent inducers. This might limit the effect of a particular senolytic compound that targets rather only a specific pathway. Interestingly, cellular senescence in prostate cancer (PCa) cells can be induced by either androgen receptor (AR) agonists at supraphysiological androgen level (SAL) used in bipolar androgen therapy or by AR antagonists. This challenges to define ligand-specific senolytic compounds.ResultsHere, we first induced cellular senescence by treating androgen-sensitive PCa LNCaP cells with either SAL or the AR antagonist Enzalutamide (ENZ). Subsequently, cells were incubated with the HSP90 inhibitor Ganetespib (GT), the Bcl-2 family inhibitor ABT263, or the Akt inhibitor MK2206 to analyze senolysis. GT and ABT263 are known senolytic compounds. We observed that GT exhibits senolytic activity specifically in SAL-pretreated PCa cells. Mechanistically, GT treatment results in reduction of AR, Akt, and phospho-S6 (p-S6) protein levels. Surprisingly, ABT263 lacks senolytic effect in both AR agonist- and antagonist-pretreated cells. ABT263 treatment does not affect AR, Akt, or S6 protein levels. Treatment with MK2206 does not reduce AR protein level and, as expected, potently inhibits Akt phosphorylation. However, ENZ-induced cellular senescent cells undergo apoptosis by MK2206, whereas SAL-treated cells are resistant. In line with this, we reveal that the pro-survival p-S6 level is higher in SAL-induced cellular senescent PCa cells compared to ENZ-treated cells. These data indicate a difference in the agonist- or antagonist-induced cellular senescence and suggest a novel role of MK2206 as a senolytic agent preferentially for AR antagonist-treated cells.ConclusionTaken together, our data suggest that both AR agonist and antagonist induce cellular senescence but differentially upregulate a pro-survival signaling which preferentially sensitize androgen-sensitive PCa LNCaP cells to a specific senolytic compound.

Dataset Information

Hits Discovery on the Androgen Receptor: In Silico Approaches to Identify Agonist Compounds.

Publications

Hits Discovery on the Androgen Receptor: In Silico Approaches to Identify Agonist Compounds.

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