Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening.

Lack, Nathan A.; Axerio-Cilies, Peter; Tavassoli, Peyman; Han, Frank Q.; Chan, Ka Hong; Féau, Clémentine; Leblanc, Éric; Guns, Emma Tomlinson; Guy, R. Kiplin; Rennie, Paul S.; Cherkasov, Artem

doi:10.1021/jm201098n

Cited by 141 publications

(131 citation statements)

References 37 publications

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“…That site is the best understood target for antiandrogen compounds (such as enzalutamide) that compete with testosterone for binding. In addition, the LBD contains alternative surface-exposed pockets such the activation-func-tion 2 (AF2) region, important for co-regulator recruitment (11), and the binding-function 3 (BF3) site of unknown function, located near the androgen-binding site (12,13). The structure of the rat AR-DBD dimer in complex with DNA has helped us to understand the role of the DBD in AR function (10).…”

Section: The Androgen Receptor (Ar)mentioning

confidence: 99%

“…Recently, using our established in silico drug design approach (13,23,24), we discovered a surface-exposed region on the AR-DBD, including residues Ser-579 to Lys-610, which was established to be targetable by small molecule inhibitors to potentially inhibit the AR by interfering with DNA binding. Computer-aided high throughput screening identified candidate molecules that were effective for abolishing AR transcriptional activity in LNCaP cells and displayed no interference or binding with the AR-LBD (25).…”

Section: The Androgen Receptor (Ar)mentioning

confidence: 99%

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

Dalal

Roshan-Moniri

Sharma

et al. 2014

Journal of Biological Chemistry

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110

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Background:The androgen receptor (AR) is a transcription factor regulating progression of prostate cancer. Results: Developed compounds inhibit AR transcriptional activity in vitro and in vivo by selective targeting of the AR-DNAbinding domain (DBD). Conclusion: By targeting the DBD, the compounds differ from conventional anti-androgens. Significance: Anti-androgens with a novel mechanism of action have the potential to treat recurrent prostate cancer.

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Section: The Androgen Receptor (Ar)mentioning

confidence: 99%

Section: The Androgen Receptor (Ar)mentioning

confidence: 99%

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

Dalal

Roshan-Moniri

Sharma

et al. 2014

Journal of Biological Chemistry

Self Cite

110

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“…Several structural scaffolds have been identified through virtual screening as binders to this BF3 region and were confirmed to have antagonistic effects not only on AR transcriptional activity (Lack et al 2011), but also on proliferation of LNCaP and enz-resistant cells (Munuganti et al 2013).…”

Section: Experimental Ar-targeted Therapiesmentioning

confidence: 99%

Androgen receptor antagonists for prostate cancer therapy

Helsen¹,

Broeck²,

Voet³

et al. 2014

Endocrine-Related Cancer

123

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Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

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“…The androgen receptor activation function 2 (AF2) specific peptide displacement was assayed as previously described (24,25).…”

Section: Chemistrymentioning

confidence: 99%

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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Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening.

Cited by 141 publications

References 37 publications

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

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

Androgen receptor antagonists for prostate cancer therapy

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

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