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1.
Nat Chem Biol ; 17(9): 947-953, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34413525

RESUMEN

Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy. Most TPD technologies use the ubiquitin-proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modular, bifunctional synthetic molecules called MoDE-As (molecular degraders of extracellular proteins through the asialoglycoprotein receptor (ASGPR)), which mediate the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and ASGPR on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing molecules that induce depletion of both antibody and proinflammatory cytokine proteins. These data show experimental evidence that nonproteinogenic, synthetic molecules can enable TPD of extracellular proteins in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.


Asunto(s)
Receptor de Asialoglicoproteína/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Dinitrofenoles/química , Dinitrofenoles/metabolismo , Células Hep G2 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química
2.
J Org Chem ; 86(12): 8479-8488, 2021 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-34047555

RESUMEN

A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones from a Suzuki cross-coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis and cyclization is described.


Asunto(s)
Nitrilos , Catálisis , Ciclización
3.
Chembiochem ; 18(15): 1551-1556, 2017 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-28470883

RESUMEN

We have investigated 4-halopyridines as selective, tunable, and switchable covalent protein modifiers for use in the development of chemical probes. Nonenzymatic reactivity of 4-chloropyridine with amino acids and thiols was ranked with respect to common covalent protein-modifying reagents and found to have reactivity similar to that of acrylamide, but could be switched to a reactivity similar to that of iodoacetamide upon stabilization of the positively charged pyridinium. Diverse, fragment-sized 4-halopyridines inactivated human dimethylarginine dimethylaminohydrolase-1 (DDAH1) through covalent modification of the active site cysteine, acting as quiescent affinity labels that required off-pathway catalysis through stabilization of the protonated pyridinium by a neighboring aspartate residue. A series of 2-fluoromethyl-substituted 4-chloropyridines demonstrated that the pKa and kinact /KI values could be predictably varied over several orders of magnitude. Covalent labeling of proteins in an Escherichia coli lysate was shown to require folded proteins, indicating that alternative proteins can be targeted, and modification is likely to be catalysisdependent. 4-Halopyridines, and quiescent affinity labels in general, represent an attractive strategy to develop reagents with switchable electrophilicity as selective covalent protein modifiers.


Asunto(s)
Amidohidrolasas/química , Piridinas/química , Acrilamida/química , Marcadores de Afinidad/química , Cisteína/química , Escherichia coli/metabolismo , Glutatión/química , Humanos , Yodoacetamida/química , Fenoles/química , Proteoma/química , Proteoma/metabolismo , Compuestos de Piridinio/química , Compuestos de Sulfhidrilo/química
4.
ACS Chem Biol ; 17(7): 1789-1798, 2022 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-35749470

RESUMEN

The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders.


Asunto(s)
Endorribonucleasas , Leucemia Mieloide Aguda , Humanos , Endorribonucleasas/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , ARN Interferente Pequeño , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau
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