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Tytuł:
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1,3,5-Triazine as a modular scaffold for covalent inhibitors with streamlined target identification.
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Autorzy:
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Banerjee R; Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.
Pace NJ
Brown DR
Weerapana E
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Źródło:
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Journal of the American Chemical Society [J Am Chem Soc] 2013 Feb 20; Vol. 135 (7), pp. 2497-500. Date of Electronic Publication: 2013 Feb 08.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Washington, DC : American Chemical Society
Original Publication: Easton, Pa. [etc.]
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MeSH Terms:
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Drug Delivery Systems*
Proteins/*antagonists & inhibitors
Small Molecule Libraries/*chemical synthesis
Triazines/*chemical synthesis
Cysteine/antagonists & inhibitors ; Cysteine/chemistry ; Electrophoresis, Polyacrylamide Gel ; HeLa Cells ; Humans ; Small Molecule Libraries/chemistry ; Triazines/chemistry
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Substance Nomenclature:
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0 (Proteins)
0 (Small Molecule Libraries)
0 (Triazines)
K848JZ4886 (Cysteine)
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Entry Date(s):
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Date Created: 20130206 Date Completed: 20130906 Latest Revision: 20131121
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Update Code:
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20240104
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DOI:
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10.1021/ja400427e
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PMID:
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23379904
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Small-molecule inhibitors can accelerate the functional annotation and validate the therapeutic potential of proteins implicated in disease. Phenotypic screens provide an effective platform to identify such pharmacological agents but are often hindered by challenges associated with target identification. For many protein targets, these bottlenecks can be overcome by incorporating electrophiles into small molecules to covalently trap interactions in vivo and by employing bioorthogonal handles to enrich the protein targets directly from a complex proteome. Here we present the trifunctionalized 1,3,5-triazine as an ideal modular scaffold for generating libraries of irreversible inhibitors with diverse target specificities. A divergent synthetic scheme was developed to derivatize the triazine with an electrophile for covalent modification of target proteins, an alkyne as a click-chemistry handle for target identification, and a diversity element to direct the compounds toward distinct subsets of the proteome. We specifically targeted our initial library toward cysteine-mediated protein activities through incorporation of thiol-specific electrophiles. From this initial screen we identified two compounds, RB-2-cb and RB-11-ca, which are cell permeable and highly selective covalent modifiers for Cys239 of β-tubulin (TUBB) and Cys53 of protein disulfide isomerase (PDI) respectively. These compounds demonstrate in vitro and cellular potencies that are comparable to currently available modulators of tubulin polymerization and PDI activity. Our studies demonstrate the versatility of the triazine as a modular scaffold to generate potent and selective covalent modifiers of diverse protein families for chemical genetics applications.