Synthesis of Biphenyl Proteomimetics as Estrogen Receptor-α Coactivator Binding Inhibitors

Williams, Amber; Weiser, Patrick T.; Hanson, Robert N.; Gunther, Jillian R.; Katzenellenbogen, John A.

doi:10.1021/ol901999f

Cited by 37 publications

(22 citation statements)

References 24 publications

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“…5,12,13,[20][21][22]24,[30][31][32] SERMs and SARMs exhibit tissueselective behaviors because of the different expression levels and cohorts of coregulatory proteins found in different tissues. 7,14,32,35,37 In this article, we reconfigured the AR-TIF2…”

Section: Discussionmentioning

confidence: 99%

“…26,35,36 Indeed, selective estrogen receptor modulators (SERMs) and selective androgen receptor modulators (SARMs) take advantage of the different repertoires and concentrations of coregulatory proteins in various cells to exert their tissue-selective behaviors. 7,14,32,35,37 SERMs and SARMS have convincingly demonstrated that small molecules can elicit tissue-or gene-selective effects, and recently, several groups have developed inhibitors that disrupt interactions between NRs and coactivator proteins. 7,14,31,32,35,37,38 For example, the bone-specific actions of the SARM S-101479 are the result of its failure to recruit TIF2, SRC-1, and NCoA3.…”

Section: Introductionmentioning

confidence: 99%

“…7,14,32,35,37 SERMs and SARMS have convincingly demonstrated that small molecules can elicit tissue-or gene-selective effects, and recently, several groups have developed inhibitors that disrupt interactions between NRs and coactivator proteins. 7,14,31,32,35,37,38 For example, the bone-specific actions of the SARM S-101479 are the result of its failure to recruit TIF2, SRC-1, and NCoA3. 38 We have previously described an AR-TIF2 PPI biosensor (PPIB) HCS assay that can be used to screen for compounds that can induce, inhibit the formation of, or disrupt preexisting PPIs between AR and TIF2.…”

Section: Introductionmentioning

confidence: 99%

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Reconfiguring the AR-TIF2 Protein–Protein Interaction HCS Assay in Prostate Cancer Cells and Characterizing the Hits from a LOPAC Screen

Fancher

Hua

Camarco

et al. 2016

ASSAY and Drug Development Technologies

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The continued activation of androgen receptor (AR) transcription and elevated expression of AR and transcriptional intermediary factor 2 (TIF2) coactivator observed in prostate cancer (CaP) recurrence and the development of castration-resistant CaP (CRPC) support a screening strategy for small-molecule inhibitors of AR-TIF2 protein-protein interactions (PPIs) to find new drug candidates. Small molecules can elicit tissue selective effects, because the cells of distinct tissues express different levels and cohorts of coregulatory proteins. We reconfigured the AR-TIF2 PPI biosensor (PPIB) assay in the PC-3 CaP cell line to determine whether AR modulators and hits from an AR-TIF2 PPIB screen conducted in U-2 OS cells would behave differently in the CaP cell background. Although we did not observe any significant differences in the compound responses between the assay performed in osteosarcoma and CaP cells, the U-2 OS AR-TIF2 PPIB assay would be more amenable to screening, because both the virus and cell culture demands are lower. We implemented a testing paradigm of counter-screens and secondary hit characterization assays that allowed us to identify and deprioritize hits that inhibited/disrupted AR-TIF2 PPIs and AR transcriptional activation (AR-TA) through antagonism of AR ligand binding or by non-specifically blocking nuclear receptor trafficking. Since AR-TIF2 PPI inhibitor/disruptor molecules act distally to AR ligand binding, they have the potential to modulate AR-TA in a cell-specific manner that is distinct from existing anti-androgen drugs, and to overcome the development of resistance to AR antagonism. We anticipate that the application of this testing paradigm to characterize the hits from an AR-TIF2 PPI high-content screening campaign will enable us to prioritize the AR-TIF2 PPI inhibitor/disruptor leads that have potential to be developed into novel therapeutics for CaP and CRPC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reconfiguring the AR-TIF2 Protein–Protein Interaction HCS Assay in Prostate Cancer Cells and Characterizing the Hits from a LOPAC Screen

Fancher

Hua

Camarco

et al. 2016

ASSAY and Drug Development Technologies

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“…Supported by theoretical data and promising results in the design of ER CBIs using biaryl scaffolds, they designed 3,3′-disubstituted bis-4,4′oxybiphenyls to mimic the hydrophobic side chains arrangement and also the electronic interactions with the charge clamp to lock the inhibitors in place (Fig 3. 4a-d) [90][91][92][93][94]. A series 3,3′-disubstituted biphenyls including 4,4′-asymmetrical phenolic-ester, amino-ester and amino-acid derivatives was prepared and their ability to disrupt ER-and AR-coactivator binding evaluated in respective cell-based transactivation assays.…”

Section: <Insert Figure 3 (Double Column)>mentioning

confidence: 99%

Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

Biron

Bédard

2016

The Journal of Steroid Biochemistry and Molecular Biology

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The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer.

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“…1b). 31 Direct inhibition of the receptor/co-activator protein-protein interaction, 32-37 notably using helix mimetics 35,36,38 is of potential therapeutic interest as an alternative to the use of competitive inhibitors for the ligand binding site. 39 Herein, we introduce two bifacial proteomimetic scaffolds; bis-benzamide and N-(4-aminophenyl)terephthalamidic as novel foldamers designed as tools to (a) enhance our understanding of aromatic oligoamide foldamer conformation and (b) ligands that could mimic the key side chains at i, i+3, i+4 positions of -helices that participate in PPIs mediated by such a side chain constellation.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and conformational analyses of bifacial benzamide based foldamers

et al. 2015

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The design, synthesis and conformational analyses of novel backbones represents a key focus of research that underpins efforts to exploit foldamers (i) in a biological setting e.g. as inibitors of protein-protien interations (PPIs) and (ii) for the purposes of constructing functional architectures that adopt defined teriary and quarternary folds. The current manuscirpt addresses a need to develop aromatic oligoamide backbones that are regiosiomeric in terms of backbone connectivity and/or functionalized on more than one face. We describe the design, synthesis and comparative conformational analyses of foldamers derived from 2-, 3-and 2,5-O-alkylated derivatives of para-aminobenzoic acid, and, derived from 2-,3-and 2,5-O-alkyalted derivatives of 1,4-diaminobenzene/terephthalic acid monomers. Analysis of the accessible conformational space for these oligomers indicates that despite different connectivity they can adopt conformations that position side chains in a manner that mimic the i, i + 3, i + 4 of an -helix.

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Synthesis of Biphenyl Proteomimetics as Estrogen Receptor-α Coactivator Binding Inhibitors

Cited by 37 publications

References 24 publications

Reconfiguring the AR-TIF2 Protein–Protein Interaction HCS Assay in Prostate Cancer Cells and Characterizing the Hits from a LOPAC Screen

Reconfiguring the AR-TIF2 Protein–Protein Interaction HCS Assay in Prostate Cancer Cells and Characterizing the Hits from a LOPAC Screen

Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

Design, synthesis and conformational analyses of bifacial benzamide based foldamers

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