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1.
Science ; 358(6367)2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29191878

RESUMO

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteômica/métodos , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Citocinas/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Camundongos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
2.
FEBS J ; 278(19): 3676-87, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21812934

RESUMO

Poly(ADP-ribose) polymerase-2 (PARP2) belongs to the ADP-ribosyltransferase family of enzymes that catalyze the addition of ADP-ribose units to acceptor proteins, thus affecting many diverse cellular processes. In particular, PARP2 shares with PARP1 and, as recently highlighted, PARP3 the sole property of being catalytically activated by DNA-strand breaks, implying key downstream functions in the cellular response to DNA damage for both enzymes. However, evidence from several studies suggests unique functions for PARP2 in additional processes, possibly mediated through its basal, DNA-damage unstimulated ADP-ribosylating activity. Here, we describe the development and application of a protein microarray-based approach tailored to identify proteins that are ADP-ribosylated by PARP2 in the absence of DNA damage mimetics and might thus represent useful entry points to the exploration of novel PARP2 functions. Several candidate substrates for PARP2 were identified and global hit enrichment analysis showed a clear enrichment in translation initiation and RNA helicase molecular functions. In addition, the top scoring candidates FK506-binding protein 3 and SH3 and cysteine-rich domain-containing protein 1 were selected and confirmed in a complementary assay format as substrates for unstimulated PARP2.


Assuntos
Dano ao DNA , Poli(ADP-Ribose) Polimerases/metabolismo , Análise Serial de Proteínas/métodos , Difosfato de Adenosina/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Humanos , Componente 2 do Complexo de Manutenção de Minicromossomo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Proteínas de Ligação a Tacrolimo/genética , Proteínas de Ligação a Tacrolimo/metabolismo
3.
Cancer Res ; 70(24): 10255-64, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21159646

RESUMO

MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Mitose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Quinazolinas/farmacologia , Fuso Acromático/efeitos dos fármacos , Aneuploidia , Animais , Antineoplásicos/química , Proteínas de Ciclo Celular/química , Processos de Crescimento Celular/efeitos dos fármacos , Células HCT116 , Células HeLa , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases , Ensaios Antitumorais Modelo de Xenoenxerto
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