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1.
Nat Biotechnol ; 34(1): 95-103, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26501955

RESUMO

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.


Assuntos
Fosfotransferases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Glicosilação
4.
Anticancer Res ; 28(4B): 2019-25, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18751369

RESUMO

BACKGROUND: Medullary thyroid cancer (MTC) is generally resistant to chemotherapy and the frequent constitutive activation of RET (rearranged during transfection gene) in these tumors might inhibit drug-induced apoptosis. MATERIALS AND METHODS: Each RET isoform was separately expressed in SK-N-MC cells (neural crest-derived tumor) and the impact of RET activation on doxorubicin-induced apoptosis was examined. RESULTS: The activation of RET9 and RET51 in the SK-N-MC cells significantly reduced the doxorubicin-induced apoptosis by 50%, compared to untreated cells. RET activation also induced phosphorylation of ERK (extracellular regulated kinase), but no changes in AKT (serine/threonine kinase) phosphorylation were noted. In the presence of a MAP (mitogen-activated protein) kinase inhibitor or a RET kinase inhibitor, the RET-activated/drug-treated cells displayed nearly 75% and 100% of the doxorubicin-induced apoptosis of the drug-treated cells without RET activation, respectively. CONCLUSION: In SK-N-MC cells, downstream activation of MAP kinase, by both RET9 and RET51, appears to mediate the majority of RET-dependent resistance to chemotherapeutically induced apoptosis. MTC might be rendered more responsive to chemotherapeutic agents by the co-administration of a RET kinase inhibitor.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/antagonistas & inibidores , Neoplasia Endócrina Múltipla Tipo 2a/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Apoptose/fisiologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Flavonoides/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasia Endócrina Múltipla Tipo 2a/tratamento farmacológico , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fosforilação , Isoformas de Proteínas , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/biossíntese , Transdução de Sinais
5.
Bioorg Med Chem Lett ; 18(16): 4610-4, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18662874

RESUMO

The synthesis of a 7-azaindole series of novel, potent B-Raf kinase inhibitors using knowledge-based design was carried out. Compound 6h exhibits not only excellent potency in both the enzyme assay (IC(50)=2.5 nM) and the cellular assay (IC(50)=63 nM), but also has an outstanding selectivity profile against other kinases.


Assuntos
Química Farmacêutica/métodos , Indóis/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Biológicos , Modelos Químicos , Estrutura Molecular , Fosfotransferases/metabolismo , Inibidores de Proteínas Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato
6.
Bioorg Med Chem Lett ; 16(17): 4686-91, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16777410

RESUMO

Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.


Assuntos
Receptores ErbB/antagonistas & inibidores , Furanos/química , Furanos/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Furanos/síntese química , Humanos , Concentração Inibidora 50 , Lapatinib , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade
7.
Curr Top Med Chem ; 6(5): 435-60, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16719802

RESUMO

Protein Kinases offer many opportunities for drug intervention points since phosphorylation is the most common post-translational modification. Phosphorylation regulates activity, location, degradation, conformation and the aberrant activity is implicated in many diseases, including cancer, inflammation, cardiovascular and central nervous system diseases. The focus of this review will be on the generation of highly effective signaling inhibitors targeting members of the erbB family of receptor tyrosine kinases, EGFR and ErbB-2, also known as transmembrane Type 1 receptor tyrosine kinases of the HER family of receptors. Ligand binding to the receptor causes a conformational change which activates the tyrosine kinase domain leading to autophosphorylation. This autophosphorylation activates the RAS/mitogen activated protein (MAP) kinase and phosphoinositol-3-kinase (PI3K) pathways leading to a myriad of signaling and cellular activities. Type 1 receptors are over-expressed in a variety of cancers and generally correlate with poor prognosis. For this reason, scientists at GlaxoSmithKline and many others in the scientific community, target the ATP binding site of the intracellular portion of the protein to block the aberrant signaling event. This review intends to cover the lessons learned in the discovery of lapatinib (GW572016, GW2016) by pulling together the various different publications that have been generated in distinct disciplines on aspects of the drug discovery program. Data analyses and correlation of assay data to help with the design of drug like molecules will be included and will demonstrate a break from the traditional focus on absolute potency as a guiding factor in lead compound selection.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Lapatinib , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
9.
Curr Top Med Chem ; 2(9): 1001-10, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12171567

RESUMO

This review covers literature describing research progress in erbB family tyrosine kinase inhibition over the last year. Excellent recent reviews are available, thus we have focussed on current developments of leading small molecule drug candidates as well as their erbB family inhibition profile. The most advanced erbB family tyrosine kinase (TK) inhibitors are demonstrating promising anti-cancer activity in clinical trials and are discussed. Several inhibition strategies are emerging: EGFR TK selective, irreversible TK inhibition and dual EGFR/erbB2 TK inhibitors. While small structural differences are seen in the leading compounds, the variations in their inhibition profiles and compound properties suggest that biological systems judge structural diversity differently. The readers' attention is drawn to common issues of selectivity and potency generally encountered with kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Oncogênicas v-erbB/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Ensaios Clínicos como Assunto , Humanos , Neoplasias/classificação , Neoplasias/enzimologia , Proteínas Oncogênicas v-erbB/classificação , Proteínas Oncogênicas v-erbB/metabolismo , Quinazolinas/química , Quinazolinas/farmacologia , Receptores Proteína Tirosina Quinases/classificação , Transdução de Sinais , Relação Estrutura-Atividade , Especificidade por Substrato
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