Publications by authors named "Brandon Dale"

6 Publications

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Advancing targeted protein degradation for cancer therapy.

Nat Rev Cancer 2021 Jun 15. Epub 2021 Jun 15.

Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The human proteome contains approximately 20,000 proteins, and it is estimated that more than 600 of them are functionally important for various types of cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional occupancy-driven pharmacology. Recent advances in the development of small-molecule degraders, including molecular glues and heterobifunctional degraders such as proteolysis-targeting chimeras (PROTACs), have made it possible to target many proteins that were previously considered undruggable. In particular, PROTACs form a ternary complex with a hijacked E3 ubiquitin ligase and a target protein, leading to polyubiquitination and degradation of the target protein. The broad applicability of this approach is facilitated by the flexibility of individual E3 ligases to recognize different substrates. The vast majority of the approximately 600 human E3 ligases have not been explored, thus presenting enormous opportunities to develop degraders that target oncoproteins with tissue, tumour and subcellular selectivity. In this Review, we first discuss the molecular basis of targeted protein degradation. We then offer a comprehensive account of the most promising degraders in development as cancer therapies to date. Lastly, we provide an overview of opportunities and challenges in this exciting field.
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http://dx.doi.org/10.1038/s41568-021-00365-xDOI Listing
June 2021

Discovery of a first-in-class EZH2 selective degrader.

Nat Chem Biol 2020 02 9;16(2):214-222. Epub 2019 Dec 9.

Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.
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http://dx.doi.org/10.1038/s41589-019-0421-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982609PMC
February 2020

Peyssonnosides A-B, Unusual Diterpene Glycosides with a Sterically Encumbered Cyclopropane Motif: Structure Elucidation Using an Integrated Spectroscopic and Computational Workflow.

J Org Chem 2019 07 18;84(13):8531-8541. Epub 2019 Jun 18.

Parker H. Petit Institute for Bioengineering and Bioscience , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

Two sulfated diterpene glycosides featuring a highly substituted and sterically encumbered cyclopropane ring have been isolated from the marine red alga Peyssonnelia sp. Combination of a wide array of 2D NMR spectroscopic experiments, in a systematic structure elucidation workflow, revealed that peyssonnosides A-B (1-2) represent a new class of diterpene glycosides with a tetracyclo [7.5.0.0.0] tetradecane architecture. A salient feature of this workflow is the unique application of quantitative interproton distances obtained from the rotating frame Overhauser effect spectroscopy (ROESY) NMR experiment, wherein the β-d-glucose moiety of 1 was used as an internal probe to unequivocally determine the absolute configuration, which was also supported by optical rotatory dispersion (ORD). Peyssonnoside A (1) exhibited promising activity against liver stage Plasmodium berghei and moderate antimethicillin-resistant Staphylococcus aureus (MRSA) activity, with no cytotoxicity against human keratinocytes. Additionally, 1 showed strong growth inhibition of the marine fungus Dendryphiella salina indicating an antifungal ecological role in its natural environment. The high natural abundance and novel carbon skeleton of 1 suggests a rare terpene cyclase machinery, exemplifying the chemical diversity in this phylogenetically distinct marine red alga.
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http://dx.doi.org/10.1021/acs.joc.9b00884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614789PMC
July 2019

American Civil War plant medicines inhibit growth, biofilm formation, and quorum sensing by multidrug-resistant bacteria.

Sci Rep 2019 05 22;9(1):7692. Epub 2019 May 22.

Center for the Study of Human Health, Emory University, Atlanta, Georgia, USA.

A shortage of conventional medicine during the American Civil War (1861-1865) spurred Confederate physicians to use preparations of native plants as medicines. In 1863, botanist Francis Porcher compiled a book of medicinal plants native to the southern United States, including plants used in Native American traditional medicine. In this study, we consulted Porcher's book and collected samples from three species that were indicated for the formulation of antiseptics: Liriodendron tulipifera, Aralia spinosa, and Quercus alba. Extracts of these species were tested for the ability to inhibit growth in three species of multidrug-resistant pathogenic bacteria associated with wound infections: Staphylococcus aureus, Klebsiella pneumoniae, and Acinetobacter baumannii. Extracts were also tested for biofilm and quorum sensing inhibition against S. aureus. Q. alba extracts inhibited growth in all three species of bacteria (IC 64, 32, and 32 µg/mL, respectively), and inhibited biofilm formation (IC 1 µg/mL) in S. aureus. L. tulipifera extracts inhibited biofilm formation (IC 32 µg/mL) in S. aureus. A. spinosa extracts inhibited biofilm formation (IC 2 µg/mL) and quorum sensing (IC 8 µg/mL) in S. aureus. These results support that this selection of plants exhibited some antiseptic properties in the prevention and management of wound infections during the conflict.
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http://dx.doi.org/10.1038/s41598-019-44242-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531439PMC
May 2019

Antibacterial Oligomeric Polyphenols from the Green Alga Cladophora socialis.

J Org Chem 2019 05 3;84(9):5035-5045. Epub 2019 Apr 3.

Aquatic Chemical Ecology Center , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

A series of oligomeric phenols including the known natural product 3,4,3',4'-tetrahydroxy-1,1'-biphenyl (3), the previously synthesized 2,3,8,9-tetrahydroxybenzo[ c]chromen-6-one (4), and eight new related natural products, cladophorols B-I (5-12), were isolated from the Fijian green alga Cladophora socialis and identified by a combination of NMR spectroscopy, mass spectrometric analysis, and computational modeling using DFT calculations. J-resolved spectroscopy and line width reduction by picric acid addition aided in resolving the heavily overlapped aromatic signals. A panel of Gram-positive and Gram-negative pathogens used to evaluate pharmacological potential led to the determination that cladophorol C (6) exhibits potent antibiotic activity selective toward methicillin-resistant Staphylococcus aureus (MRSA) with an MIC of 1.4 μg/mL. Cladophorols B (5) and D-H (7-11) had more modest but also selective antibiotic potency. Activities of cladophorols A-I (4-12) were also assessed against the asexual blood stages of Plasmodium falciparum and revealed cladophorols A (4) and B (5) to have modest activity with EC values of 0.7 and 1.9 μg/mL, respectively.
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http://dx.doi.org/10.1021/acs.joc.8b03218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503470PMC
May 2019

Antibacterial Activity of and Against ESKAPE Pathogens.

Front Pharmacol 2019 6;10:67. Epub 2019 Feb 6.

Center for the Study of Human Health, Emory College of Arts and Sciences, Atlanta, GA, United States.

Plants in the genus (Family: Crassulaceae) are used in traditional medicine throughout the tropics for treating a variety of conditions. Two species, and , have established ethnobotanical usage but have been neglected in previous research concerning their potential bioactivity. Here, we provide a thorough review of the reported antimicrobial activities of genus and evaluate the antibacterial effects of two previously unexplored species against a panel of multidrug-resistant bacteria, the ESKAPE pathogens (, and ). Plant specimens were collected and voucher specimens deposited in the Emory University Herbarium. Dried plant material was ground into a powder and extracted as ethanolic macerations or as aqueous decoctions. Extracts were tested against the ESKAPE pathogens for growth inhibitory activity. Cytotoxicity to human cells was assessed via a lactate dehydrogenase assay of treated human keratinocytes (HaCaTs). extracts demonstrated growth inhibitory effects against two Gram-negative species, (strain CDC-33) and (AH-71), as well as (UAMS-1). In these cases, growth inhibition greater than 50% (IC) was generally observed at concentrations of 256 μg mL, though one extract (1465, prepared from stems) exhibited an IC against at 128 μg mL. All extracts were well tolerated by HaCaTs (LD ≥ 256 μg mL). Chemical characterization using HPLC and chemical standards established the presence of caffeic acid and quercetin in both plant species, as well as kaempferol in These results reveal to be a plant of medicinal interest, and future research should aim to characterize the bioactivity of this species and its active constituents through bioassay-guide fractionation. Effects on bacterial biofilm formation and quorum-sensing are also research topics of interest for this genus.
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http://dx.doi.org/10.3389/fphar.2019.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374630PMC
February 2019