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VPC-13822 - A Novel Nonsteroidal Drug for the Treatment of Castration Resistant Prostate Cancer by Blocking the Binding Function-3 of the Human Androgen Receptor.

ABSTRACT: Inhibition of the alternative target site Binding Function-3 (BF3) of the androgen receptor (AR) with small molecules may represent a novel and viable option for treating castration-resistant disease. In vitro transcription assays and microsome stability experiments were used to characterize the latest and most optimized AR BF3 inhibitor compound VPC-13789 to determine its anti-AR activity and pharmacokinetic properties. VPC-13789 selectively inhibited AR-mediated transcription with an IC50 value of 0.2 μM and effectively supressed the growth of androgen-stimulated LNCaP cell line with an IC50 of 0.32 μM while having no effect on AR-negative PC3 cells. We have further synthesized a pro-drug of VPC-13789 (VPC-13822) with improved solubility and bioavailability. The VPC-13822 pro-drug was evaluated for 4 weeks in mice xenograft LNCaP castration resistant model. When administered orally, VPC-13822 significantly reduced PSA production and tumor volume in this prostate cancer model. No signs of generic toxicity of the candidate compound were observed. Taken together, these results establish a novel class of orally available AR inhibitors with a completely distinct mode of action with a potential utility to treat drug-resistant forms of prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147811 | GEO | 2022/04/05

REPOSITORIES: GEO

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Project description:The androgen receptor (AR) is a mediator of both androgen-dependent and castration- resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells. HIPK2 and MED19 were identified via a genome-wide RNAi screen as new androgen receptor (AR) reulators. Our goal in performing this microarray was to identify the gene regulated by HIPK2 and MED19 in a late stage prostate cancer cell line (LNCaP-abl), and to see what genes are in common with known genes to be regulated by AR, and what genes are unique to HIPK2 or MED19. Knockdown of HIPK2 and MED19 was tested in LNCaP-abl cells against control. Each was performed in duplicates. Six samples were analyzed

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VPC-13822 - A Novel Nonsteroidal Drug for the Treatment of Castration Resistant Prostate Cancer by Blocking the Binding Function-3 of the Human Androgen Receptor.

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