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; Hassona, Mohamed D.H.; Hsing, Michael; Singh, Kriti; Leblanc, Éric; Dehm, Scott M.; Guns, Emma S. Tomlinson; Cherkasov, Artem; Rennie, Paul S.

doi:10.1074/jbc.a117.553818

Cited by 29 publications

(57 citation statements)

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“…EPI-506 is an NTD inhibitor that can bind both AR-Vs and AR-FL and is currently under evaluation in phase I clinical trials (NCT02606123) (Maughan and Antonarakis 2015). Other potentially attractive therapeutic targets include the DBD (Dalal et al 2014) and sites of AR cofactor interaction (Ravindranathan et al 2013). In summary, our progressive understanding of the potential molecular mechanisms through which AR may drive transcriptional programming continues to guide the development of novel strategies to disrupt AR signaling.…”

Section: Androgen Signaling In Prostate Cancermentioning

confidence: 99%

Androgen Signaling in Prostate Cancer

Dai

Heemers

Sharifi

2017

Cold Spring Harb Perspect Med

295

242

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The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, progression to castration-resistant prostate cancer (CRPC) typically follows and is largely the result of restored androgen signaling. Efforts to understand the mechanisms behind CRPC have revealed new insights into dysregulated androgen signaling and intratumoral androgen synthesis, which has ultimately led to the development of several novel androgen receptor (AR)-directed therapies for CRPC. However, emergence of resistance to these newer agents has also galvanized new directions in investigations of prereceptor and postreceptor AR regulation. Here, we review our current understanding of AR signaling as it pertains to the biology and natural history of prostate cancer.

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Section: Androgen Signaling In Prostate Cancermentioning

confidence: 99%

Androgen Signaling in Prostate Cancer

Dai

Heemers

Sharifi

2017

Cold Spring Harb Perspect Med

295

242

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“…17,18 This drug was approved by the FDA in 2012 for mCRPC with progression after docetaxel. In the AFFIRM trial, 1199 patients who were previously treated with a docetaxel chemotherapy were randomly assigned into enzalutamide or placebo.…”

Section: Enzalutamidementioning

confidence: 99%

Current treatment strategies for advanced prostate cancer

et al. 2017

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During the past decade, treatment strategies for patients with advanced prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone-sensitive prostate cancer and recurrent prostate cancer after treatment with curative intent, as well as castration-resistant prostate cancer, have extensively evolved with the introduction and approval of several new agents including sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, all of which have shown significant improvement on overall survival. The appropriate use of these agents and the proper sequencing of these agents are still not optimized. The results of several recently reported randomized controlled trials and retrospective studies could assist in developing a treatment strategy for advanced prostate cancer. In addition, prospective studies and molecular characterization of tumors to address these issues are ongoing.

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“…A correction to the published structure of VPC-14449 was made in 2017 (20,21). Pyrvinium pamoate was purchased from Enamine (Monmouth Jct., NJ).…”

Section: Methodsmentioning

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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Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer.

Cited by 29 publications

References 0 publications

Androgen Signaling in Prostate Cancer

Androgen Signaling in Prostate Cancer

Current treatment strategies for advanced prostate cancer

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

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