Inhibitors of Androgen Receptor Activation Function-2 (AF2) Site Identified through Virtual Screening

Axerio-Cilies, Peter; Lack, Nathan A.; Nayana, M. Ravi Shashi; Chan, Ka Hong; Yeung, Anthony T.; Leblanc, Éric; Guns, Emma S. Tomlinson; Rennie, Paul S.; Cherkasov, Artem

doi:10.1021/jm200532b

Cited by 86 publications

(96 citation statements)

References 24 publications

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“…In addition, out of the large number of chemicals screened in silico, only a small subset of chemicals is tested to quantify biological activity based on the computational prediction results. These substantial advantages have made the VS approach increasingly valuable for the identification of novel lead scaffolds that bind to ligand-dependent receptors (30,31).…”

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confidence: 99%

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

Song

Yang

Park

et al. 2012

Journal of Biological Chemistry

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Background:The androgen receptor (AR) is the primary drug target for prostate cancer treatment. Results: We have identified a novel AR antagonist, the compound 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) that inhibits the growth of AR-positive prostate cancer cells. Conclusion: DIMN has been identified as a new lead structure targeting the AR. Significance: This novel AR antagonist could be a useful therapeutic agent for prostate cancer treatment.

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confidence: 99%

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

Song

Yang

Park

et al. 2012

Journal of Biological Chemistry

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“…These compounds did not affect SRC2-3 peptide displacement, suggesting they do not interact with the AF2 coactivation site of the androgen receptor (data not shown; ref. 24).…”

Section: Resultsmentioning

confidence: 99%

“…The direct reversible interaction between small molecules and the androgen receptor was measured as previously described (24).…”

Section: Chemistrymentioning

confidence: 99%

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Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer

Hassona

Lack

et al. 2013

Molecular Cancer Therapeutics

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The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the androgen receptor is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of androgen receptor antagonists that could help overcome the problem of resistance. In this study, we implemented and used the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H-anthracen-9-ones that not only effectively inhibit androgen receptor transcriptional activity, but also induce almost complete degradation of the androgen receptor. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that showed strong androgen displacement potency, effectively inhibited androgen receptor transcriptional activity, and possesses a profound ability to cause degradation of androgen receptor. Notably, VPC-3033 exhibited significant activity against prostate cancer cells that have already developed resistance to the second-generation antiandrogen enzalutamide (formerly known as MDV3100). VPC-3033 also showed strong antiandrogen receptor activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of androgen receptor antagonists that can help address the problem of antiandrogen resistance in prostate cancer. Mol Cancer Ther; 12(11); 2425-35. Ó2013 AACR.

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“…Another recent study provided evidence that FKBP52, a co-chaperone protein critical for maintaining AR in a conformation competent for ligand binding, may interact with AR through the BF-3 domain [26]. Importantly, these critical AF-2/BF-3 mediated functions are amenable to targeting with small molecules [23,[26][27][28] which could potentially lead to new avenues of AR-targeted therapy.…”

Section: Structure and Function Of The Ar Cooh-terminal Domainmentioning

confidence: 99%

Androgen Receptor Gene Rearrangements: New Perspectives on Prostate Cancer Progression

Brand¹,

Dehm²

2013

CDT

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The androgen receptor (AR) is a master regulator transcription factor in normal and cancerous prostate cells. Canonical AR activation requires binding of androgen ligand to the AR ligand binding domain, translocation to the nucleus, and transcriptional activation of AR target genes. This regulatory axis is targeted for systemic therapy of advanced prostate cancer. However, a new paradigm for AR activation in castration-resistant prostate cancer (CRPC) has emerged wherein alternative splicing of AR mRNA promotes synthesis of constitutively active AR variants that lack the AR ligand binding domain (LBD). Recent work has indicated that structural alteration of the AR gene locus represents a key mechanism by which alterations in AR mRNA splicing arise. In this review, we examine the role of truncated AR variants (ARVs) and their corresponding genomic origins in models of prostate cancer progression, as well as the challenges they pose to the current standard of prostate cancer therapies targeting the AR ligand binding domain. Since ARVs lack the COOH-terminal LBD, the genesis of these AR gene rearrangements and their resulting ARVs provides strong rationale for the pursuit of new avenues of therapeutic intervention targeted at the AR NH 2 -terminal domain. We further suggest that genomic events leading to ARV expression could act as novel biomarkers of disease progression that may guide the optimal use of current and next-generation AR-targeted therapy.

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Inhibitors of Androgen Receptor Activation Function-2 (AF2) Site Identified through Virtual Screening

Cited by 86 publications

References 24 publications

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer

Androgen Receptor Gene Rearrangements: New Perspectives on Prostate Cancer Progression

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