Selectively Targeting the DNA-binding Domain of the Androgen Receptor as a Prospective Therapy for Prostate Cancer

Dalal, Kush; Roshan-Moniri, Mani; Sharma, Aishwariya; Li, Huifang; Ban, Fuqiang; Hessein, Mohamed; Hsing, Michael; Singh, Kriti; Leblanc, Éric; Dehm, Scott M.; Guns, Emma S. Tomlinson; Cherkasov, Artem; Rennie, Paul S.

doi:10.1074/jbc.m114.553818

Cited by 109 publications

(88 citation statements)

References 47 publications

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“…Therefore, more effective AR inhibitors may also be associated with increased toxicity (especially if they potentially penetrate the blood-brain barrier). Novel compounds (e.g., EPI-001) that bind to the N-terminal domain of the AR and interfere with protein-protein interaction may be promising new approaches [25,26].…”

Section: Discussionmentioning

confidence: 99%

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

et al. 2015

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Section: Discussionmentioning

confidence: 99%

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

et al. 2015

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“…Mutations in the AR-LBD or -DBD in hAR WT of were generated using a QuikChange kit (Agilent). PIPE cloning (19) was used to replace the AR-DBD with the rat glucocorticoid receptor (GR) DBD, yielding ARw/GRDBD as outlined in Table S1. A plasmid encoding the GST-tagged rat C552A AR-DBD mutant was previously described (13).…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, we analyzed the crystal structure of the AR-DBD:DNA complex to identify a surface exposed pocket near the protein-DNA interface that could be targeted with small molecules (18,19). The lead compound, VPC-14449, potently inhibited full-length AR in LNCaP cells, down-regulated PSA expression and suppressed growth of xenografts in mouse models (19). However, the mechanism of action of VPC-14449 has not been fully defined.…”

Section: Introductionmentioning

confidence: 99%

Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor–Chromatin Interactions

Dalal¹,

Xia

Que

et al. 2017

Molecular Cancer Therapeutics

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Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug-target in the treatment of prostate cancer. Current small molecule AR-antagonists, such as enzalutamide, compete with androgens that bind to the steroid binding pocket of the AR ligand binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug-resistance can manifest through AR-LBD mutations that convert AR-antagonists into agonists, or by expression of AR-variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the development a series of small molecules that were rationally designed to selectively target the AR DNA binding domain (DBD) and, hence, to directly interfere with AR-DNA interactions. In the current work we have confirmed that the lead AR DBD inhibitor indeed directly interacts with the AR-DBD and tested that substance across multiple clinically relevant CRPC cell lines. We have also performed a series of experiments that revealed that genome-wide chromatin binding of AR was dramatically impacted by the lead compound (although with lesser effect on AR variants). Collectively, these observations confirm the novel mechanism of anti-androgen action of the developed AR-DBD inhibitors, establishing proof-of-principle for targeting DNA-binding domains of nuclear receptors in endocrine cancers.

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“…Similar approaches in which the Oct1 binding site of a representative AR target gene was targeted also prevented Oct1-dependent transcription as well as the growth of CaP xenografts (Obinata et al 2016). Alternatively, a small molecule that selectively binds a surface exposed pocket on AR-DBD effectively blocked transcriptional activity of full length AR and constitutively active AR splice variants (Dalal et al 2014). Targeting what were previously viewed as undruggable interactions within transcriptional complexes provides proof-of-principle for development of novel compounds that inhibit critical protein-protein and protein-DNA interactions that are most relevant to AR-mediated lethal CaP progression.…”

Section: Different Molecular Modes Of Ar Action: Opportunities For Nomentioning

confidence: 99%

“…Other targets in the pathways leading to aberrant AR activation such as interference with the chaperone proteins clusterin or Sigma-1 (Thomas, et al 2017; Yamamoto, et al 2015), or with the signaling cascade by which cytokines or growth factors activate AR activity (Culig 2004), to name but a few, have been explored also for therapeutic intervention. Parallel efforts have focused on targeting for therapy AR moieties other than its ligand-binding domain, such as its constitutively active N-terminal transactivation domain (Andersen, et al 2010; Myung, et al 2013) or its DNA binding-domain (Dalal, et al 2014). The latter approaches have either not been tested yet in clinical trials or the results of such trials are not yet available.…”

Section: Introductionmentioning

confidence: 99%

Rationale for the development of alternative forms of androgen deprivation therapy

Kumari¹,

Senapati²,

Heemers³

2017

Endocrine-Related Cancer

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With few exceptions, the almost 30,000 prostate cancer deaths annually in the United States are due to failure of androgen deprivation therapy. Androgen deprivation therapy prevents ligand-activation of the androgen receptor. Despite initial remission after androgen deprivation therapy, prostate cancer almost invariably progresses while continuing to rely on androgen receptor action. Androgen receptor's transcriptional output, which ultimately controls prostate cancer behavior, is an alternative therapeutic target, but its molecular regulation is poorly understood. Recent insights in the molecular mechanisms by which the androgen receptor controls transcription of its target genes are uncovering gene specificity as well as context-dependency. Heterogeneity in the androgen receptor's transcriptional output is reflected both in its recruitment to diverse cognate DNA binding motifs and in its preferential interaction with associated pioneering factors, other secondary transcription factors and coregulators at those sites. This variability suggests that multiple, distinct modes of androgen receptor action that regulate diverse aspects of prostate cancer biology and contribute differentially to prostate cancer's clinical progression are active simultaneously in prostate cancer cells. Recent progress in the development of peptidomimetics and small molecules, and application of Chem-Seq approaches indicate the feasibility for selective disruption of critical protein-protein and protein-DNA interactions in transcriptional complexes. Here, we review the recent literature on the different molecular mechanisms by which the androgen receptor transcriptionally controls prostate cancer progression, and we explore the potential to translate these insights into novel, more selective forms of therapies that may bypass prostate cancer's resistance to conventional androgen deprivation therapy.

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Selectively Targeting the DNA-binding Domain of the Androgen Receptor as a Prospective Therapy for Prostate Cancer

Cited by 109 publications

References 47 publications

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor–Chromatin Interactions

Rationale for the development of alternative forms of androgen deprivation therapy

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