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1.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361750

RESUMO

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from Acacia auriculiformis stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/ß (GSK-3 α/ß), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia.


Assuntos
Acacia/química , Antineoplásicos Fitogênicos/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/genética , Sítios de Ligação , Caseína Quinase Iépsilon/antagonistas & inibidores , Caseína Quinase Iépsilon/genética , Caseína Quinase Iépsilon/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Células K562 , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismo , Casca de Planta/química , Extratos Vegetais/química , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Proteínas Proto-Oncogênicas c-abl/química , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Transdução de Sinais , Triterpenos/química , Triterpenos/isolamento & purificação , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Nat Commun ; 12(1): 4536, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315872

RESUMO

Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically "hot" pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Imunidade , Quinases Relacionadas a NIMA/antagonistas & inibidores , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Modelos Biológicos , Quinases Relacionadas a NIMA/deficiência , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Fosfosserina/metabolismo , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteólise , Ubiquitinação
3.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072728

RESUMO

Ovarian cancer is often detected at the advanced stages at the time of initial diagnosis. Early-stage diagnosis is difficult due to its asymptomatic nature, where less than 30% of 5-year survival has been noticed. The underlying molecular events associated with the disease's pathogenesis have yet to be fully elucidated. Thus, the identification of prognostic biomarkers as well as developing novel therapeutic agents for targeting these markers become relevant. Herein, we identified 264 differentially expressed genes (DEGs) common in four ovarian cancer datasets (GSE14407, GSE18520, GSE26712, GSE54388), respectively. We constructed a protein-protein interaction (PPI) interaction network with the overexpressed genes (72 genes) and performed gene enrichment analysis. In the PPI networks, three proteins; TTK Protein Kinase (TTK), NIMA Related Kinase 2 (NEK2), and cyclin-dependent kinase (CDK1) with higher node degrees were further evaluated as therapeutic targets for our novel multi-target small molecule NSC777201. We found that the upregulated DEGs were enriched in KEGG and gene ontologies associated with ovarian cancer progression, female gamete association, otic vesicle development, regulation of chromosome segregation, and therapeutic failure. In addition to the PPI network, ingenuity pathway analysis also implicate TTK, NEK2, and CDK1 in the elevated salvage pyrimidine and pyridoxal pathways in ovarian cancer. The TTK, NEK2, and CDK1 are over-expressed, demonstrating a high frequency of genetic alterations, and are associated with poor prognosis of ovarian cancer cohorts. Interestingly, NSC777201 demonstrated anti-proliferative and cytotoxic activities (GI50 = 1.6 µM~1.82 µM and TGI50 = 3.5 µM~3.63 µM) against the NCI panels of ovarian cancer cell lines and exhibited a robust interaction with stronger affinities for TTK, NEK2, and CDK1, than do the standard drug, paclitaxel. NSC777201 displayed desirable properties of a drug-like candidate and thus could be considered as a novel small molecule for treating ovarian carcinoma.


Assuntos
Biologia Computacional , Descoberta de Drogas , Perfilação da Expressão Gênica , Variação Genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Inibidores de Proteínas Quinases/química , Biomarcadores Tumorais , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Biologia Computacional/métodos , Descoberta de Drogas/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/química , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Relação Estrutura-Atividade , Transcriptoma
4.
Int Immunopharmacol ; 95: 107576, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33770730

RESUMO

Inflammation is involved in noise-induced hearing loss (NIHL), but the mechanism is still unknown. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which triggers the inflammatory cascade, has been implicated in several inflammatory diseases in response to oxidative stress. However, whether the NLRP3 inflammasome is a key factor for permanent NIHL is still unknown. In this study, quantitative real-time polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assays (ELISAs) demonstrated that the expression levels of activated caspase-1, interleukin (IL)-1ß, IL-18, and NLRP3 were significantly increased in the cochleae of mice exposed to broadband noise (120 dB) for 4 h, compared with the control group. These results indicate that the activation of inflammasomes in the cochleae of mice during the pathological process of NIHL as well as NLRP3, a sensor protein of reactive oxygen species (ROS), may be key factors for inflammasome assembly and subsequent inflammation in cochleae. Moreover, many recent studies have revealed that NEK7 is an important component and regulator of NLRP3 inflammasomes by interacting with NLRP3 directly and that these interactions can be interrupted by oridonin. Here, we further determined that treatment with oridonin could indeed interrupt the interaction between NLRP3 and NEK7 as well as inhibit the downstream inflammasome activation in mouse cochleae after noise exposure. Furthermore, we tested anakinra, another inflammatory inhibitor, and it was shown to partially alleviate the degree of hearing impairment in some frequencies in an NIHL mouse model. These discoveries suggest that inhibiting NLRP3 inflammasomes and the downstream signaling pathway may provide a new strategy for the clinical treatment of NIHL.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diterpenos do Tipo Caurano/uso terapêutico , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Cóclea/efeitos dos fármacos , Cóclea/imunologia , Citocinas/imunologia , Diterpenos do Tipo Caurano/farmacologia , Perda Auditiva Provocada por Ruído/imunologia , Inflamassomos/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Camundongos Endogâmicos C57BL , Quinases Relacionadas a NIMA/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia
5.
J Med Chem ; 64(1): 768-781, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33440945

RESUMO

Berberine (BBR), a traditional Chinese medicine, has therapeutic effects on a variety of inflammation-related diseases, but its direct proteomic targets remain unknown. Using activity-based protein profiling, we first demonstrated that BBR directly targets the NEK7 protein via the hydrogen bond between the 2,3-methylenedioxy and 121-arginine (R121) residues. The fact that R121 is located precisely within the key domain involved in the NEK7-NLRP3 interaction allows BBR to specifically block the NEK7-NLRP3 interaction and successively inhibit IL-1ß release, independent of the NF-κB and TLR4 signaling pathways. Moreover, BBR displays in vivo anti-inflammatory efficacy in a NEK7-dependent manner. Therefore, we consider NEK7 to be a key target of BBR in the treatment of NLRP3-related inflammatory diseases, and the development of novel NEK7-NLRP3 interaction inhibitors might be easily achieved using NEK7 as a target.


Assuntos
Anti-Inflamatórios/química , Berberina/química , Quinases Relacionadas a NIMA/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Berberina/metabolismo , Berberina/farmacologia , Sítios de Ligação , Humanos , Ligação de Hidrogênio , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/química , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
6.
Int J Mol Sci ; 22(2)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435251

RESUMO

Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4' of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC50~1 µM) with moderate selectivity over other kinases.


Assuntos
Benzilaminas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/enzimologia , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinazolinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzilaminas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Mutação , Proteínas de Neoplasias/antagonistas & inibidores , Quinazolinas/uso terapêutico , Relação Estrutura-Atividade
7.
Breast Cancer Res ; 22(1): 133, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33267874

RESUMO

BACKGROUND: Mutations in one allele of the TP53 gene in early stages are frequently followed by the loss of the remaining wild-type p53 (wtp53) allele (p53LOH) during tumor progression. Despite the strong notion of p53LOH as a critical step in tumor progression, its oncogenic outcomes that facilitate the selective pressure for p53LOH occurrence were not elucidated. METHODS: Using MMTV;ErbB2 mouse model of breast cancer carrying heterozygous R172H p53 mutation, we identified a novel gain-of-function (GOF) activity of mutant p53 (mutp53): the exacerbated loss of wtp53 allele in response to γ-irradiation. RESULTS: As consequences of p53LOH in mutp53 heterozygous cells, we observed profound stabilization of mutp53 protein, the loss of p21 expression, the abrogation of G2/M checkpoint, chromosomal instability, centrosome amplification, and transcriptional upregulation of mitotic kinase Nek2 (a member of Never in Mitosis (NIMA) Kinases family) involved in the regulation of centrosome function. To avoid the mitotic catastrophe in the absence of G2/M checkpoint, cells with centrosome amplification adapt Nek2-mediated centrosomes clustering as pro-survival mutp53 GOF mechanism enabling unrestricted proliferation and clonal expansion of cells with p53LOH. Thus, the clonal dominance of mutp53 cells with p53LOH may represent the mechanism of irradiation-induced p53LOH. We show that pharmacological and genetic ablation of Nek2 decreases centrosome clustering and viability of specifically mutp53 cells with p53LOH. CONCLUSION: In a heterogeneous tumor population, Nek2 inhibition may alter the selective pressure for p53LOH by contraction of the mutp53 population with p53LOH, thus, preventing the outgrowth of genetically unstable, more aggressive cells.


Assuntos
Neoplasias da Mama/genética , Perda de Heterozigosidade/genética , Quinases Relacionadas a NIMA/genética , Proteína Supressora de Tumor p53/genética , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Centrossomo/metabolismo , Instabilidade Cromossômica , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Mutação com Ganho de Função , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Perda de Heterozigosidade/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Quinases Relacionadas a NIMA/antagonistas & inibidores , Receptor ErbB-2/genética , Ativação Transcricional , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
8.
Bioorg Med Chem ; 28(23): 115775, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32992252

RESUMO

Never in mitosis (NIMA) related kinase 2 (Nek2) is involved in multiple cellular processes such as cell cycle checkpoint regulation, cell division, DNA damage response and cell apoptosis. Nek2 has been reported to be overexpressed in various tumors and correlated with poor prognosis. Herein, a series of imidazo[1,2-a] pyridines Nek2 inhibitors were designed, synthesized, and their biological activities were investigated. Besides, structure activity relationship analysis of these compounds were performed in the MGC-803 cell. The screening results are promising, and compound 28e shows good proliferation inhibitory activity with an IC50 of 38 nM. The results would be helpful to design and develop more effective Nek2 inhibitors for the treatment of gastric cancer.


Assuntos
Desenho de Fármacos , Quinases Relacionadas a NIMA/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Piridinas/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Quinases Relacionadas a NIMA/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Relação Estrutura-Atividade
9.
Biochem Pharmacol ; 177: 113998, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32353421

RESUMO

Disordered immune regulation and persistent inflammatory damage are the key mechanisms of ventilator-induced lung injury (VILI). NLR family pyrin domain containing 3 (NLRP3) inflammasome activation causes VILI by mediating the formation of inflammatory mediators and infiltration of inflammatory cells, increasing pulmonary capillary membrane permeability, which leads to pulmonary edema and lung tissue damage. What mediates activation of NLRP3 inflammasome in VILI? In this study, we constructed an in vitro cyclic stretch (CS)-stimulated mouse lung epithelial (MLE-12) cell model that was transfected with NIMA-related kinase 7 (NEK7) small interfering RNA (siRNA) or scramble siRNA (sc siRNA) and pretreated with or without glibenclamide (glb). We also established a VILI mouse model, which was pretreated with glibenclamide or oridonin (Ori). Our goal was to investigate the regulatory effects of NEK7 on NLRP3 inflammasome activation and the anti-inflammatory effects of glibenclamide and oridonin on VILI. Mechanical stretch exaggerated the interaction between NEK7 and NLRP3, leading to assembly and activation of NLRP3 inflammasome downstream of potassium efflux. NEK7 depletion and treatment with glibenclamide or oridonin exerted anti-inflammatory effects that alleviated VILI by blocking the interaction between NEK7 and NLRP3, inhibiting NLRP3 inflammasome activation. NEK7 is a vital mediator of NLRP3 inflammasome activation, and glibenclamide or oridonin may be candidates for the development of new therapeutics against VILI driven by the interaction between NEK7 and NLRP3.


Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Glibureto/farmacologia , Quinases Relacionadas a NIMA/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Fenômenos Biomecânicos , Cátions Monovalentes , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Transporte de Íons/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Potássio/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Respiração Artificial/efeitos adversos , Transdução de Sinais , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia
10.
Biosci Trends ; 14(2): 74-82, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32295992

RESUMO

NLRP3 inflammasome plays an essential role in innate immunity, yet the activation mechanism of NLRP3 inflammasome is not clear. In human or animal models, inappropriate NLRP3 inflammasome activation is implicated in many NLRP3-related diseases, such as tumors, inflammatory diseases and autoimmune diseases. Until now, a great number of inhibitors have been used to disturb the related signaling pathways, such as IL-1ß blockade, IL-18 blockade and caspase-1 inhibitors. Unfortunately, most of these inhibitors just disturb the signaling pathways after the activation of NLRP3 inflammasome. Inhibitors that directly regulate NLRP3 to abolish the inflammation response may be more effective. NEK7 is a multifunctional kinase affecting centrosome duplication, mitochondrial regulation, intracellular protein transport, DNA repair and mitotic spindle assembly. Researchers have made significant observations on the regulation of gene transcription or protein expression of the NLRP3 inflammasome signaling pathway by NEK7. Those signaling pathways include ROS signaling, potassium efflux, lysosomal destabilization, and NF-κB signaling. Furthermore, NEK7 has been proved to be involved in many NLRP3-related diseases in humans or in animal models. Inhibitors focused on NEK7 may regulate NLRP3 to abolish the inflammation response and NEK7 may be a potential therapeutic target for NLRP3-related diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Inflamação/tratamento farmacológico , Quinases Relacionadas a NIMA/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Doenças Autoimunes/imunologia , Modelos Animais de Doenças , Imunidade Inata/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/imunologia , Camundongos , Terapia de Alvo Molecular/métodos , Quinases Relacionadas a NIMA/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
11.
Molecules ; 25(8)2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32294979

RESUMO

In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.


Assuntos
Doenças do Sistema Nervoso Central/enzimologia , Ciliopatias/enzimologia , Diabetes Mellitus/enzimologia , Inflamação/enzimologia , Quinases Relacionadas a NIMA/metabolismo , Neoplasias/enzimologia , Animais , Proteínas de Ciclo Celular/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Ciliopatias/metabolismo , Diabetes Mellitus/metabolismo , Humanos , Inflamação/metabolismo , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/genética , Neoplasias/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/genética
12.
Eur J Med Chem ; 191: 112118, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113126

RESUMO

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Proteínas do Citoesqueleto/antagonistas & inibidores , Descoberta de Drogas , Quinases Relacionadas a NIMA/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinases Relacionadas a NIMA/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Distribuição Tecidual
13.
Cancer Res ; 80(8): 1693-1706, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32054769

RESUMO

A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer (TNBC), a disease commonly treated with these drugs. Here, we report that LIN9 is further elevated with acquisition of taxane resistance. Inhibiting LIN9 genetically or by suppressing its expression with a global BET inhibitor restored taxane sensitivity by inducing mitotic progression errors and apoptosis. While sustained LIN9 is necessary to maintain taxane resistance, there are no inhibitors that directly repress its function. Hence, we sought to discover a druggable downstream transcriptional target of LIN9. Using a computational approach, we identified NIMA-related kinase 2 (NEK2), a regulator of centrosome separation that is also elevated in taxane-resistant cells. High expression of NEK2 was predictive of low survival rates in patients who had residual disease following treatment with taxanes plus an anthracycline, suggesting a role for this kinase in modulating taxane sensitivity. Like LIN9, genetic or pharmacologic blockade of NEK2 activity in the presence of paclitaxel synergistically induced mitotic abnormalities in nearly 100% of cells and completely restored sensitivity to paclitaxel, in vitro. In addition, suppressing NEK2 activity with two distinct small molecules potentiated taxane response in multiple in vivo models of TNBC, including a patient-derived xenograft, without inducing toxicity. These data demonstrate that the LIN9/NEK2 pathway is a therapeutically targetable mediator of taxane resistance that can be leveraged to improve response to this core chemotherapy. SIGNIFICANCE: Resistance to chemotherapy is a major hurdle for treating patients with cancer. Combining NEK2 inhibitors with taxanes may be a viable approach for improving patient outcomes by enhancing mitotic defects induced by taxanes alone.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Paclitaxel/farmacologia , Taxoides/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Senescência Celular , Centrossomo/enzimologia , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Xenoenxertos , Humanos , Mitose/genética , Quinases Relacionadas a NIMA/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Taxoides/administração & dosagem , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Ensaio Tumoral de Célula-Tronco , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
14.
Biochem Biophys Res Commun ; 517(2): 338-345, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31358323

RESUMO

OBJECTIVE: Artemisinin is a potent anti-malarial agent that plays a potent role in regulating inflammatory disorders. NEK7 is a major interacting partner with NLRP3 in NLRP3 inflammasome. The aim of this study was to clarify the anti-inflammatory effect of artemisinin on activation of uric acid-induced NLRP3 inflammasome through regulation of NEK7. METHODS: Human macrophage U937 cells treated with lipopolysaccharide (LPS), monosodium urate (MSU) crystals, or artemisinin were used in in vitro study. Intracellular potassium (K+) level was measured in U937 cells treated with and without artemisinin. Expression of target genes or proteins NEK7, NLRP3, ASC, caspase-1, interleukin-1ß (IL-1ß), and NF-κB signaling molecules was measured. MSU crystal-induced arthritis model was used for in vivo study. RESULTS: Gout patients showed higher NLRP3 and NEK7 mRNA expression, compared to controls. Enhanced expression of NLRP3, caspase-1, and IL-1ß was noted in macrophages treated with LPS (10 ng/ml) and MSU crystals (0.1 mg/ml), which was markedly suppressed by treatment with artemisinin (1, 10, and 100 µM). Artemisinin significantly inhibited interaction between NLRP3 and NEK7 in NLRP3 inflammasome activation. Artemisinin (10 and 100 µM) attenuated intracellular K+ efflux in macrophages stimulated with LPS and MSU crystals. Artemisinin suppressed foot and ankle swelling in MSU crystal-induced arthritis mice. CONCLUSION: This study revealed that artemisinin inhibited activation of NLRP3 inflammasome by suppressing interaction between NEK7 and NLRP3 in uric acid-induced inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Artemisininas/farmacologia , Inflamação/tratamento farmacológico , Quinases Relacionadas a NIMA/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ácido Úrico/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Artemisininas/uso terapêutico , Artrite/tratamento farmacológico , Artrite/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/imunologia , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores
15.
Anticancer Res ; 39(5): 2251-2258, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092416

RESUMO

Cancer is characterized by uncontrolled cell proliferation due to the aberrant activity of various proteins. Cell cycle-related proteins are thought to be important in several functions, such as proliferation, invasion and drug resistance in human malignancies. Never in mitosis gene A-related kinase 2 (NEK2) is a cell cycle-related protein. NEK2 is highly expressed in various tumor types and cancer cell lines. NEK2 expression is correlated with rapid relapse and poor outcome in multiple cancer types. Several researchers have demonstrated that NEK2 inhibition results in anticancer effects against many types of cancers, both in vitro and in vivo. Recent research strongly indicates the advantages of NEK2-targeted therapy for cancer. This review focuses on the current understanding of NEK2 in cancer and the rationale of a xenograft cancer model for cancer treatment. A possible therapeutic strategy, such as inhibitor and nucleic acid medicine targeting of NEK2, is also discussed.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Quinases Relacionadas a NIMA/genética , Neoplasias/genética , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Humanos , Camundongos , Mitose/genética , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Sci Rep ; 8(1): 16047, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375481

RESUMO

The NIMA (never in mitosis, gene A)-related kinase-6 (NEK6), which is implicated in cell cycle control and plays significant roles in tumorigenesis, is an attractive target for the development of novel anti-cancer drugs. Here we describe the discovery of a potent ATP site-directed inhibitor of NEK6 identified by virtual screening, adopting both structure- and ligand-based techniques. Using a homology-built model of NEK6 as well as the pharmacophoric features of known NEK6 inhibitors we identified novel binding scaffolds. Twenty-five compounds from the top ranking hits were subjected to in vitro kinase assays. The best compound, i.e. compound 8 ((5Z)-2-hydroxy-4-methyl-6-oxo-5-[(5-phenylfuran-2-yl)methylidene]-5,6-dihydropyridine-3-carbonitrile), was able to inhibit NEK6 with low micromolar IC50 value, also displaying antiproliferative activity against a panel of human cancer cell lines. Our results suggest that the identified inhibitor can be used as lead candidate for the development of novel anti-cancer agents, thus opening the possibility of new therapeutic strategies.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular Tumoral , Descoberta de Drogas/métodos , Ativação Enzimática , Humanos , Concentração Inibidora 50 , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/química , Quinases Relacionadas a NIMA/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Relação Estrutura-Atividade
17.
Nat Commun ; 9(1): 2550, 2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959312

RESUMO

Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori's anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Gotosa/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diterpenos do Tipo Caurano/farmacologia , Quinases Relacionadas a NIMA/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Peritonite/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Artrite Gotosa/genética , Artrite Gotosa/imunologia , Artrite Gotosa/patologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Diterpenos do Tipo Caurano/isolamento & purificação , Regulação da Expressão Gênica , Humanos , Inflamassomos/química , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamação , Isodon/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Peritonite/genética , Peritonite/imunologia , Peritonite/patologia , Extratos Vegetais/química , Ligação Proteica , Transdução de Sinais
18.
J Clin Invest ; 128(7): 2877-2893, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29863498

RESUMO

Drug resistance remains the key problem in cancer treatment. It is now accepted that each myeloma patient harbors multiple subclones and subclone dominance may change over time. The coexistence of multiple subclones with high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. In this study, using a tandem affinity purification-mass spectrometry (TAP-MS) technique, we found that NEK2, a CIN gene, was bound to the deubiquitinase USP7. Binding to USP7 prevented NEK2 ubiquitination resulting in NEK2 stabilization. Increased NEK2 kinase levels activated the canonical NF-κB signaling pathway through the PP1α/AKT axis. Newly diagnosed myeloma patients with activated NF-κB signaling through increased NEK2 activity had poorer event-free and overall survivals based on multiple independent clinical cohorts. We also found that NEK2 activated heparanase, a secreted enzyme, responsible for bone destruction in an NF-κB-dependent manner. Intriguingly, both NEK2 and USP7 inhibitors showed great efficacy in inhibiting myeloma cell growth and overcoming NEK2-induced and -acquired drug resistance in xenograft myeloma mouse models.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Quinases Relacionadas a NIMA/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Técnicas de Silenciamento de Genes , Glucuronidase/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Modelos Biológicos , Mieloma Múltiplo/patologia , NF-kappa B/metabolismo , Quinases Relacionadas a NIMA/antagonistas & inibidores , Prognóstico , Ligação Proteica , Estabilidade Proteica , Transdução de Sinais , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Peptidase 7 Específica de Ubiquitina/genética , Peptidase 7 Específica de Ubiquitina/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Phys Chem Chem Phys ; 20(8): 5591-5605, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29270587

RESUMO

NIMA-related kinase 2 (Nek2) plays a significant role in cell cycle regulation, and overexpression of Nek2 has been observed in several types of carcinoma, suggesting it is a potential target for cancer therapy. In this study, we attempted to gain more insight into the binding mechanisms of a series of aminopyrazine inhibitors of Nek2 through multiple molecular modeling techniques, including molecular docking, molecular dynamics (MD) simulations and free energy calculations. The simulation results showed that the induced fit docking and ensemble docking based on multiple protein structures yield better predictions than conventional rigid receptor docking, highlighting the importance of incorporating receptor flexibility into the accurate predictions of the binding poses and binding affinities of Nek2 inhibitors. Additionally, we observed that the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations did not show better performance than the docking scoring to rank the binding affinities of the studied inhibitors, suggesting that MM/GBSA is system-dependent and may not be the best choice for the Nek2 systems. Moreover, the detailed information on protein-ligand binding was characterized by the MM/GBSA free energy decomposition, and a number of derivatives with improved docking scores were designed. It is expected that our study can provide valuable information for the future rational design of novel and potent inhibitors of Nek2.


Assuntos
Quinases Relacionadas a NIMA/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Quinases Relacionadas a NIMA/metabolismo , Inibidores de Proteínas Quinases/química , Pirazinas/química , Termodinâmica
20.
Mol Oncol ; 12(1): 74-88, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29112787

RESUMO

Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics, we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival. A role for NEK9 in the growth of NRAS- and KRAS-mutant cell lines was suggested by siRNA studies in which silencing was associated with decreased proliferation, cell cycle arrest associated with increased p21 expression, inhibition of phospho-CHK1, decreased CDK4 expression, and the initiation of a senescence response. Inhibition of CDK4 but not CHK1 recapitulated the effects of NEK9 silencing, indicating this to be the likely mechanism of growth inhibition. We next turned our attention to CDK16 and found that its knockdown inhibited the phosphorylation of the Rb protein at S780 and increased expression of p27. Both of these effects were phenocopied in NRAS- and KRAS-mutant cancer cells by dabrafenib, but not vemurafenib. Combined silencing of NEK9 and CDK16 was associated with enhanced inhibition of melanoma cell proliferation. In summary, we have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations.


Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Imidazóis/farmacologia , Melanoma/tratamento farmacológico , Quinases Relacionadas a NIMA/antagonistas & inibidores , Oximas/farmacologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/genética , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Quinases Relacionadas a NIMA/genética , Oximas/administração & dosagem , Oximas/uso terapêutico , Proteômica , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
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