4,4′-Unsymmetrically substituted 3,3′-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors

Weiser, Patrick T.; Chang, Ching‐yi; McDonnell, Donald P.; Hanson, Robert N.

doi:10.1016/j.bmc.2013.10.051

Cited by 12 publications

(6 citation statements)

References 27 publications

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“…Benzhydryl alcohol 5 reacted with alkynyltrifluoroborate in the presence of HBF 4 to afford alkyne 6 . Demethylation and cyclization proceeded under the reported conditions.…”

mentioning

confidence: 99%

Brønsted Acid-Catalyzed Reactions of Trifluoroborate Salts with Benzhydryl Alcohols

Fisher

Bolshan

2015

J. Org. Chem.

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Brønsted acid-catalyzed carbon-carbon bond forming methodology using potassium alkynyl- and alkenyltrifluoroborate salts has been developed. Organotrifluoroborates react with benzhydryl alcohols to afford a broad range of alkynes and alkenes in good to excellent yields. This protocol features good atom economy because organotrifluoroborate salts and alcohols react in a 1:1 ratio. Furthermore, a variety of unprotected functional groups were tolerated under the developed conditions, including amide, aldehyde, free hydroxyl, and carboxylic acid.

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“…Benzhydryl alcohol 5 reacted with alkynyltrifluoroborate in the presence of HBF 4 to afford alkyne 6 . Demethylation and cyclization proceeded under the reported conditions.…”

mentioning

confidence: 99%

Brønsted Acid-Catalyzed Reactions of Trifluoroborate Salts with Benzhydryl Alcohols

Fisher

Bolshan

2015

J. Org. Chem.

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“…Much of the characterization for these molecules has been restricted to in vitro studies (see [17, 40] for reviews of the literature), and of those molecules that have cellular characterization, there are several common features: many are active in reporter gene and mammalian two-hybrid assays, but whether they can repress the activity of native genes or breast cancer phenotypes regulated by ER is unknown. [41] [42] There are a few exceptions, including peptides synthesized by Brunsveld and coworkers, [13] as well as Li and coworkers[43], although even these most advanced examples have been characterized using only one native gene.…”

Section: Discussionmentioning

confidence: 99%

A Cell-Permeable Stapled Peptide Inhibitor of the Estrogen Receptor/Coactivator Interaction

et al. 2018

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We and others have proposed that coactivator binding inhibitors, which block the interaction of estrogen receptor and steroid receptor coactivators, may represent a potential class of new breast cancer therapeutics. The development of coactivator binding inhibitors has been limited, however, because many of the current molecules which are active in in vitro and biochemical assays are not active in cell-based assays. Our goal in this work was to prepare a coactivator binding inhibitor active in cellular models of breast cancer. To accomplish this, we used molecular dynamics simulations to convert a high-affinity stapled peptide with poor cell permeability into R4K1, a cell-penetrating stapled peptide. R4K1 displays high binding affinity for estrogen receptor α, inhibits the formation of estrogen receptor/coactivator complexes, and distributes throughout the cell with a high percentage of nuclear localization. R4K1 represses native gene transcription mediated by estrogen receptor α and inhibits proliferation of estradiol-stimulated MCF-7 cells. Using RNA-Seq, we demonstrate that almost all of the effects of R4K1 on global gene transcription are estrogen-receptor-associated. This chemical probe provides a significant proof-of-concept for preparing cell-permeable stapled peptide inhibitors of the estrogen receptor/coactivator interaction.

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“…Further exploration of the SAR has solely focused on activity against ERα. 62 Compound 7b has a high cLogP value, 12 rotatable bonds, and an iPFI >7. Considering the presence of a basic amine and its comparatively high lipophilicity, the molecule is likely to exhibit off-target liabilities, demonstrated by the cytotoxicity of structurally related analogs.…”

Section: Activation Function 2-targeting Compoundsmentioning

confidence: 99%

“… 53 Various substitution patterns on the biaryl linker resulted in cytotoxicity at concentrations above 50 µM. Further exploration of the SAR has solely focused on activity against ERα 62 …”

Section: Activation Function 2‐targeting Compoundsmentioning

confidence: 99%

Current and emerging approaches to noncompetitive AR inhibition

Riley

Elwood

Henry

et al. 2023

Medicinal Research Reviews

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The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration‐resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand‐binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.

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4,4′-Unsymmetrically substituted 3,3′-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors

Cited by 12 publications

References 27 publications

Brønsted Acid-Catalyzed Reactions of Trifluoroborate Salts with Benzhydryl Alcohols

Brønsted Acid-Catalyzed Reactions of Trifluoroborate Salts with Benzhydryl Alcohols

A Cell-Permeable Stapled Peptide Inhibitor of the Estrogen Receptor/Coactivator Interaction

Current and emerging approaches to noncompetitive AR inhibition

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