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1.
J Med Chem ; 62(24): 11232-11259, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31724864

RESUMO

The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.


Assuntos
Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Ácido Salicílico/química , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligação Proteica , Conformação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Repetições WD40
2.
Mol Cell ; 58(3): 440-52, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25818646

RESUMO

MYC is an oncoprotein transcription factor that is overexpressed in the majority of malignancies. The oncogenic potential of MYC stems from its ability to bind regulatory sequences in thousands of target genes, which depends on interaction of MYC with its obligate partner, MAX. Here, we show that broad association of MYC with chromatin also depends on interaction with the WD40-repeat protein WDR5. MYC binds WDR5 via an evolutionarily conserved "MYC box IIIb" motif that engages a shallow, hydrophobic cleft on the surface of WDR5. Structure-guided mutations in MYC that disrupt interaction with WDR5 attenuate binding of MYC at ∼80% of its chromosomal locations and disable its ability to promote induced pluripotent stem cell formation and drive tumorigenesis. Our data reveal WDR5 as a key determinant for MYC recruitment to chromatin and uncover a tractable target for the discovery of anticancer therapies against MYC-driven tumors.


Assuntos
Carcinogênese/metabolismo , Cromatina/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Anisotropia , Sítios de Ligação/genética , Carcinogênese/genética , Cromatina/química , Cromatina/genética , Polarização de Fluorescência , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Nus , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Células NIH 3T3 , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas/química , Proteínas/genética , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/genética , Homologia de Sequência de Aminoácidos , Técnicas do Sistema de Duplo-Híbrido
3.
Mol Cell Proteomics ; 9(10): 2162-72, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20562096

RESUMO

The ability to obtain in-depth understanding of signaling networks in cells is a key objective of systems biology research. Such ability depends largely on unbiased and reproducible analysis of phosphoproteomes. We present here a novel proteomics tool, polymer-based metal ion affinity capture (PolyMAC), for the highly efficient isolation of phosphopeptides to facilitate comprehensive phosphoproteome analyses. This approach uses polyamidoamine dendrimers multifunctionalized with titanium ions and aldehyde groups to allow the chelation and subsequent isolation of phosphopeptides in a homogeneous environment. Compared with current strategies based on solid phase micro- and nanoparticles, PolyMAC demonstrated outstanding reproducibility, exceptional selectivity, fast chelation times, and high phosphopeptide recovery from complex mixtures. Using the PolyMAC method combined with antibody enrichment, we identified 794 unique sites of tyrosine phosphorylation in malignant breast cancer cells, 514 of which are dependent on the expression of Syk, a protein-tyrosine kinase with unusual properties of a tumor suppressor. The superior sensitivity of PolyMAC allowed us to identify novel components in a variety of major signaling networks, including cell migration and apoptosis. PolyMAC offers a powerful and widely applicable tool for phosphoproteomics and molecular signaling.


Assuntos
Nanoestruturas , Fosfoproteínas/química , Polímeros/química , Proteoma , Titânio/química , Western Blotting , Linhagem Celular Tumoral , Humanos , Imunoprecipitação , Reprodutibilidade dos Testes , Solubilidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
4.
Mol Cancer Res ; 7(5): 634-44, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19435818

RESUMO

The expression of the Syk protein tyrosine kinase in breast cancer cells is inversely correlated with invasive growth and metastasis. The expression of Syk inhibits cell motility while supporting the formation of cell clusters by enhancing cell-cell contacts and promoting the redistribution of the adhesion proteins cortactin and vinculin to these contacts. Syk associates physically with cortactin and catalyzes its phosphorylation on tyrosine. The clustering of integrins leads to the phosphorylation of Syk and of numerous cellular proteins in a manner dependent on the activity of the kinase and on the presence of tyrosine 342 located in the linker B region. The ability of Syk to participate in integrin-mediated protein tyrosine phosphorylation correlates well with its ability to inhibit cell motility.


Assuntos
Comunicação Celular/fisiologia , Movimento Celular/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Tirosina Quinases/metabolismo , Sítios de Ligação , Western Blotting , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Cortactina/metabolismo , Reagentes de Ligações Cruzadas/química , Citoplasma/metabolismo , Ativação Enzimática , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Integrinas/química , Integrinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Microscopia de Fluorescência , Fosforilação , Ligação Proteica , Transporte Proteico , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Quinase Syk , Transfecção , Tirosina/metabolismo , Vinculina/metabolismo
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