RESUMO
Honokiol, derived from Magnolia officinalis (a traditional Chinese medicine), has been reported to have anticancer activity. Here, a series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared and evaluated for their anticancer activities against three types of digestive system tumor cells. Biological evaluation showed that honokiol derivative 3k exhibited the best antiproliferative activity against HCT116 cells with an IC50 value of 6.1 µmol/L, superior to the reference drug 5-fluorouracil (IC50: 9.63 ± 0.27 µmol/L). The structure-activity relationships (SARs) indicated that the introduction of -(4-NO2)Ph, 3-pyridyl, -(2-F)Ph, -(4-F)Ph, -(3-F)Ph, -(4-Cl)Ph, and -(3-Cl)Ph groups was favorable for enhancing the anticancer activity of the title honokiol thioethers. Further study revealed that honokiol thioether 3k can well inhibit the proliferation of colon cancer cells HCT116, arresting the cells in G1 phase and inducing cell death. Moreover, a preliminary mechanism study indicated that 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Thus, honokiol thioether 3k could be deeply developed for the development of honokiol-based anticancer candidates.
Assuntos
Compostos de Bifenilo , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Lignanas , Proteínas de Sinalização YAP , Humanos , Lignanas/farmacologia , Lignanas/química , Lignanas/síntese química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Proteínas de Sinalização YAP/metabolismo , Estrutura Molecular , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Sulfetos/química , Sulfetos/farmacologia , Sulfetos/síntese química , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/síntese química , Relação Dose-Resposta a Droga , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Compostos Alílicos , FenóisRESUMO
Overactivation of neddylation has been found in a number of common human tumor-related diseases. In recent years, targeting the neddylation pathway has become an appealing anti-cancer strategy, and it is critical to find neddylation inhibitors with novel structures and higher efficacy. Here, we present the discovery of novel inhibitors of the NEDD8-activating enzyme (NAE) and their antitumor activity in vitro. All synthesized 1,4-disubstituted piperidine compounds were evaluated for antiproliferative activity against MGC-803, MCF-7, A549, and KYSE-30 cells. Among five representative compounds, III-26 bearing a quinazoline motif was identified as the lead one due to the fact that it significantly hindered the neddylation of Cullin1. Cellular mechanisms elucidated that III-26 inhibited the proliferation, migration, and invasion of UBC12-overexpressed MGC-803 cell lines, as well as induced apoptosis and arrested the cell cycle at G2/M phase. Importantly, III-26 reduced NAE activity, thus selectively preventing neddylation of Cullin3 and Cullin1 over other Cullin members. At a dose of 4 µM, III-26 virtually entirely blocked UBC12-NEDD8 conjugation in MGC-803 cells. Our molecular modeling and kinetic investigation suggested that this compound may function as a non-covalent inhibitor of NAE.
Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , ApoptoseRESUMO
Epigenetic regulation and Focal adhesion kinase (FAK) are considered to be two important targets for the development of antitumor drugs. Studies have shown that the combination of FAK and HDAC inhibitors could exhibit synergistic effects in a subset of cancer cells in vitro and in vivo. At present, there are few reports on dual target inhibitors of FAK and HDAC. Here, we first reported a new compound MY-1259 as a dual FAK and HDAC6 inhibitor, which exhibited efficient treatment effects on gastric cancers in vitro and in vivo. MY-1259 exhibited potent inhibitory activities against FAK (IC50 = 132 nM) and HDAC6 (IC50 = 16 nM). Notably, MY-1259 showed selective inhibitory potency on HDAC6 over HDAC1, HDAC2 and HDAC3. In addition, MY-1259 could potently inhibit the proliferative activities of MGC-803 and BGC-823 cells (IC50 = 3.91 and 15.46 nM, respectively, using flow cytometry counting), induce cell apoptosis, and cellular senescence. MY-1259 could effectively down-regulate the levels of Ac-Histone H3 and Ac-α-tubulin, and also inhibit the phosphorylation of FAK at three phosphorylation sites Y397, Y576/577 and Y925, thereby inhibiting the activation of ERK and AKT/mTOR. MY-1259 exhibited more effective antitumor effect in vivo than the HDAC inhibitor SAHA and FAK inhibitor TAE-226 alone or in combination, showing the advantages of FAK/HDAC dual inhibitors in the treatment of gastric cancers. Therefore, the results in this work suggested that inhibition of FAK and HDAC by MY-1259 might represent a promising strategy for the treatment of gastric cancers.
Assuntos
Antineoplásicos , Proteína-Tirosina Quinases de Adesão Focal , Inibidores de Histona Desacetilases , Neoplasias Gástricas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Epigênese Genética , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
In this study, twenty-one novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors targeting FAK were designed and synthesized based on the structure of TAE-226, and the inhibitory effects of these compounds on both the FAK enzyme and three cancer cell lines (MGC-803, HCT-116, and KYSE30) were investigated. Among them, compound 12s displayed potent inhibitory potency on FAK (IC50 = 47 nM), and demonstrated more significant antiproliferative activities in MGC-803, HCT-116 and KYSE30 cells (IC50 values were 0.24, 0.45 and 0.44 µM, respectively) compared to TAE-226. Furthermore, compound 12s significantly inhibited FAK activation leading to the negative regulation of FAK-related signaling pathways such as AKT/mTOR and MAPK signaling pathways. Molecular docking study suggested that compound 12s could well occupy the ATP-binding pocket site of FAK similar to TAE-226. In addition, compound 12s also efficiently inhibited the proliferation, induced apoptosis and cellular senescence in MGC-803 cells. In conclusion, compound 12s emerges a potent FAK inhibitor that could exert potent inhibitory activity against gastric cancer cells.
Assuntos
Antineoplásicos , Neoplasias Gástricas , Humanos , Relação Estrutura-Atividade , Antineoplásicos/química , Simulação de Acoplamento Molecular , Neoplasias Gástricas/tratamento farmacológico , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Linhagem Celular Tumoral , Inibidores de Proteínas QuinasesRESUMO
The microtubule system plays an important role in the mitosis and growth of eukaryotic cells, and it is considered as an appealing and highly successful molecular target for cancer treatment. In fact, microtubule targeting agents, such as paclitaxel and vinblastine, have been approved by FDA for tumor therapy, which have achieved significant therapeutic effects and sales performance. At present, microtubule targeting agents mainly include microtubule-destabilizing agents, microtubule-stabilizing agents, and a few tubulin degradation agents. Although there are few reports about tubulin degradation agents at present, tubulin degradation agents show great potential in overcoming multidrug resistance and reducing neurotoxicity. In addition, some natural drugs could specifically degrade tubulin in tumor cells, but have no effect in normal cells, thus showing a good biosafety profile. Therefore, tubulin degradation agents might exhibit a better application. Currently, some small molecules have been designed to promote tubulin degradation with potent antiproliferative activities, showing the potential for cancer treatment. In this work, we reviewed the reports on tubulin degradation, and focused on the degradation mechanism and important functional groups of chemically synthesized compounds, hoping to provide help for the degradation design of tubulin.
Assuntos
Antineoplásicos , Tubulina (Proteína) , Tubulina (Proteína)/metabolismo , Microtúbulos , Antineoplásicos/química , Vimblastina/metabolismo , Vimblastina/farmacologia , Paclitaxel/metabolismo , Moduladores de Tubulina/químicaRESUMO
As a class of microtubule targeting agents, colchicine binding site inhibitors (CBSIs) are considered as promising drug candidates for cancer therapy. However, due to adverse reactions, there are currently no CBSIs approved by FDA for cancer treatment. Therefore, extensive efforts are still encouraged to find novel CBSIs with different chemical structures and better anticancer efficacies. In this work, we designed and synthesized a new coumarin-dihydroquinoxalone derivative, MY-673, and evaluated its anticancer potency in vitro and in vivo. We confirmed that MY-673 was a potent CBSI that it not only inhibited tubulin polymerization, but also exhibited significant inhibitory potency on the growth of 13 cancer cells with IC50 values from 11.7 nM to 395.9 nM. Based on the results of kinase panel screening, MY-673 could inhibit ERK (extracellular regulated protein kinases) pathways-related kinases. We further confirmed that MY-673 could inhibit ERK signaling pathway in MGC-803 and HGC-27 cells, and then affected the expression level of SMAD4 protein in TGF-ß (transforming growth factor ß) /SMAD (small mother against decapentaplegic) signaling pathway using the western blotting assay. In addition, compound MY-673 could effectively inhibit cell proliferation, migration and induce cell apoptosis. We also further confirmed the in vivo efficacy of MY-673 in inhibiting tumor growth using the MGC-803 xenograft tumor model. At 20 mg/kg, the TGI rate was 85.9%, and it did not cause obvious toxicity to the main organs of mice. Together, the results we report here indicated that MY-673 was a promising CBSI for cancer treatment, which was capable of inhibiting the ERK pathway with potent antiproliferative activities in vitro and in vivo.
Assuntos
Antineoplásicos , Neoplasias Gástricas , Humanos , Animais , Camundongos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico , Moduladores de Tubulina/química , Sistema de Sinalização das MAP Quinases , Tubulina (Proteína)/metabolismo , Microtúbulos , Colchicina/metabolismo , Proliferação de Células , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-AtividadeRESUMO
Vascular epidermal growth factor receptor-2 (VEGFR-2), as an important tyrosine transmembrane protein, plays an important role in regulating endothelial cell proliferation and migration, regulating angiogenesis and other biological functions. VEGFR-2 is aberrantly expressed in many malignant tumors, and it is also related to the occurrence, development, and growth of tumors and drug resistance. Currently, there are nine VEGFR-2 targeted inhibitors approved by US.FDA for clinical use as anticancer drugs. Due to the limited clinical efficacy and potential toxicity of VEGFR inhibitors, it is necessary to develop new strategies to improve the clinical efficacy of VEGFR inhibitors. The development of multitarget therapy, especially dual-target therapy, has become a hot research field of cancer therapy, which may provide an effective strategy with higher therapeutic efficacy, pharmacokinetic advantages and low toxicity. Many groups have reported that the therapeutic effects could be improved by simultaneously inhibiting VEGFR-2 and other targets, such as EGFR, c-Met, BRAF, HDAC, etc. Therefore, VEGFR-2 inhibitors with multi-targeting capabilities have been considered to be promising and effective anticancer agents for cancer therapy. In this work, we reviewed the structure and biological functions of VEGFR-2, and summarized the drug discovery strategies, and inhibitory activities of VEGFR-2 inhibitors with multi-targeting capabilities reported in recent years. This work might provide the reference for the development of VEGFR-2 inhibitors with multi-targeting capabilities as novel anticancer agents.
Assuntos
Antineoplásicos , Neoplasias , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Proliferação de Células , Descoberta de Drogas , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
In this work, a series of novel arylamide derivatives containing piperazine moiety were designed and synthesised as tubulin polymerisation inhibitors. Among 25 target compounds, compound 16f (MY-1121) exhibited low nanomolar IC50 values ranging from 0.089 to 0.238 µM against nine human cancer cells. Its inhibitory effects on liver cancer cells were particularly evident with IC50 values of 89.42 and 91.62 nM for SMMC-7721 and HuH-7 cells, respectively. Further mechanism studies demonstrated that compound 16f (MY-1121) could bind to the colchicine binding site of ß-tubulin and directly act on ß-tubulin, thus inhibiting tubulin polymerisation. Additionally, compound 16f (MY-1121) could inhibit colony forming ability, cause morphological changes, block cell cycle arrest at the G2 phase, induce cell apoptosis, and regulate the expression of cell cycle and cell apoptosis related proteins in liver cancer cells. Overall, the promising bioactivities of compound 16f (MY-1121) make the novel arylamide derivatives have the value for further development as tubulin polymerisation inhibitors with potent anticancer activities.
Assuntos
Neoplasias Hepáticas , Tubulina (Proteína) , Humanos , Apoptose , Sítios de Ligação , Piperazina , Moduladores de TubulinaRESUMO
Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However, for its high-risk type, even with various intensive treatment options, the prognosis is still unsatisfactory. At the same time, a large number of research data show that the abnormal amplification and high-level expression of the MYCN gene are positively correlated with the malignant progression, poor prognosis, and mortality of neuroblastoma. In this context, this article explores the role of the N-Myc, MYCN gene expression product on its target genes related to the cell cycle and reveals its regulatory network in promoting tumor proliferation and malignant progression. We hope it can provide ideas and direction for the research and development of drugs targeting N-Myc and its downstream target genes.
Assuntos
Neuroblastoma , Proteínas Nucleares , Humanos , Proteínas Nucleares/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Genes myc , Ciclo Celular/genética , Neuroblastoma/patologia , Regulação Neoplásica da Expressão Gênica , Linhagem Celular TumoralRESUMO
In order to find high-efficiency and low-toxic anti-tumor drugs, 29 pyrido[3,4-d]pyrimidine compounds were designed, synthesized and evaluated by MTT assay in vitro. The results presented that most of the compounds had good antitumor activities, among which compound 30 had the best anti-tumor activity on MGC803 cells (IC50 = 0.59 µM). Mechanistic studies exhibited that compound 30 inhibited migration of MGC803 and induced apoptosis. It was proved that compound 30 up-regulated expression of Bid and PARP, down-regulated expression of CycD1 by western blot experiments. This study indicated that compound 30 might be served as a lead agent for the treatment of human gastric cancers.
Assuntos
Antineoplásicos , Apoptose , Pirimidinas , Humanos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Poli(ADP-Ribose) Polimerases/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Background: Seed abortion is a common phenomenon in Chinese jujube that seriously hinders the process of cross-breeding. However, the molecular mechanisms of seed abortion remain unclear in jujube. Methods: Here, we performed transcriptome sequencing using eight flower and fruit tissues at different developmental stages in Ziziphus jujuba Mill. 'Zhongqiusucui' to identify key genes related to seed abortion. Histological analysis revealed a critical developmental process of embryo abortion after fertilization. Results: Comparisons of gene expression revealed a total of 14,012 differentially expressed genes. Functional enrichment analyses of differentially expressed genes between various sample types uncovered several important biological processes, such as embryo development, cellular metabolism, and stress response, that were potentially involved in the regulation of seed abortion. Furthermore, gene co-expression network analysis revealed a suite of potential key genes related to ovule and seed development. We focused on three types of candidate genes, agamous subfamily genes, plant ATP-binding cassette subfamily G transporters, and metacaspase enzymes, and showed that the expression profiles of some members were associated with embryo abortion. Conclusion: This work generates a comprehensive gene expression data source for unraveling the molecular mechanisms of seed abortion and aids future cross-breeding efforts in jujube.
RESUMO
[1,2,4]Triazolo[1,5-a]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compounds H1-H18 against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compound H12 exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC50 values of 9.47, 9.58 and 13.1 µM, respectively, which were more potent than that of the positive drug 5-Fu. In addition, compound H12 could dose-dependently inhibit the growth and colony formation of MGC-803 cells. Compound H12 exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound 12 induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound, H12, might be a valuable hit compound for the development of anticancer agents.
Assuntos
Antineoplásicos , Neoplasias Gástricas , Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases , Estrutura Molecular , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Tubulin, an important target in tumor therapy, is one of the hotspots in the field of antineoplastic drugs in recent years, and it is of great significance to design and screen new inhibitors for this target. Natural products and chemical synthetic drugs are the main sources of tubulin inhibitors. However, due to the variety of compound structure types, it has always been difficult for researchers to screen out polymerization inhibitors with simple operation, high efficiency and low cost. A large number of articles have reported the screening methods of tubulin inhibitors and their biological activity. In this article, the biological activity detection methods of tubulin polymerization inhibitors are reviewed. Thus, it provides a theoretical basis for the further study of tubulin polymerization inhibitors and the selection of methods for tubulin inhibitors.
Assuntos
Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Humanos , Polimerização/efeitos dos fármacos , Moduladores de Tubulina/químicaRESUMO
Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 µM (MGC-803 cells), 6.82 µM (A549 cells), 1.61 µM (Kyse30 cells), 1.49 µM (Kyse450 cells), 2.08 µM (Kyse510 cells) and 2.24 µM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of ß-tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in time and dose-dependent manners. All the results suggest that the indoline derivatives might be a class of novel tubulin inhibitors with potential anticancer activity and is worthy of further study.
RESUMO
Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 µM (MGC-803 cells), 6.82 µM (A549 cells), 1.61 µM (Kyse30 cells), 1.49 µM (Kyse450 cells), 2.08 µM (Kyse510 cells) and 2.24 µM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in a time and dose-dependent manner. All the results suggest that the indoline derivatives may be a class of novel tubulin inhibitors with potential anticancer activity, and which is worthy of further study.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Indóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib, the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure-activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
NEDDylation is a post-translational modification of a protein, which transfers Ubiquitin like protein NEDD8 (Neuronal Precursor Cell-expressed Developmentally Down-regulated Protein 8) to the lysine residue of the product through a three-stage enzymatic reaction, and widely regulates many biological processes, such as cell cycle signal transduction and immune recognition. In the past ten years, we have witnessed tremendous progress in the study of protein ubiquitination modification, from modification mechanisms to drug development. Which suggests that inhibition of NEDDylation is an effective way to inhibit tumor. A variety of biological detection methods have been developed during the development of the inhibitor. In this review, we briefly introduced the modification process and substrates of NEDDylation, and discussed detection methods of NEDDylation activity in detail. This review will provide an up-to-date and comprehensive review of the methods for detecting NEDDylation activity that will contribute to NEDDylation inhibitor development.
Assuntos
Antineoplásicos/farmacologia , Proteína NEDD8/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Humanos , Proteína NEDD8/metabolismo , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacosRESUMO
A series of novel indole derivatives were synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (MGC803, EC-109 and PC-3). Among these analogues, 2-(5-methoxy-1H-indol-1-yl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (V7) showed the best inhibitory activity against MGC803 cells with an IC50 value of 1.59 µM. Cellular mechanisms elucidated that V7 inhibited colony formation, induced apoptosis and arrested cell cycle at G2/M phase. Importantly, indole analogue V7 inhibited NEDDylation pathway and MAPK pathway against MGC803 cells.
Assuntos
Antineoplásicos/farmacologia , Indóis/química , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Indóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Enzimas de Conjugação de Ubiquitina/metabolismoRESUMO
Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 µM (MGC-803 cells), 0.70 µM (HCT-116 cells), 1.04 µM (PC-3 cells), and 0.81 µM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.
Assuntos
Antineoplásicos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação da Expressão Gênica/efeitos dos fármacos , Via de Sinalização Hippo , Humanos , Camundongos Nus , Estrutura Molecular , Quinazolinas/síntese química , Transdução de Sinais , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Pesticide residues have become a healthy threaten of human beings. Among the pesticides, many of them have neurotoxicity. Extracellular Regulated Protein Kinases (ERK) pathway is an important signaling pathway that regulates a variety of downstream progress. In this work, peach (PRUNUS persica) and cherry (PRUNUS cerasus) were sampled from over 300 plantations in China and assessed for the residue risk. In mechanism studies, high-risk pesticide Avermectin showed a high activity inhibiting three neurotoxicity models, SH-SY5Y, PC-12 and SK-N-SH cells. At protein levels, ERK pathway proteins and their downstream proteins were obviously down-regulated. Moreover, the effects of low-dose Avermectin can be accumulated at protein levels in the low-dose long-term chronic toxicology detection.