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1.
Eur J Med Chem ; 177: 448-456, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174062

RESUMO

The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis-trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special water-bridged hydrogen bonds. The structure also provided guidance for the structural optimization of this type of CSI, which led to the discovery of the most potent inhibitor A3, with growth IC50 lower than 1 nM against human colon cancer cell lines and tubulin polymerization IC50 of 1.6 µM. In addition, its water-soluble prodrug B1 showed good in vivo antitumor activity on two human colon cancer xenograft nude mice models, encouraging further study of this type of antitumor compound.


Assuntos
Antineoplásicos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Indazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Feminino , Células HCT116 , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ligação Proteica/efeitos dos fármacos , Solubilidade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Eur J Med Chem ; 178: 232-242, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185413

RESUMO

As a continuation to our research, a series of novel Bcr-Abl inhibitors incorporated with 6-phenyl-1H-indazol-3-amine as hinge binding moiety (HBM) were developed based on confirmation analysis. Biological results indicated that these compounds exhibited an enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in kinases assays, along with improved anti-proliferative activities in K562 cell assays. In particular, compound Y9 displayed comparable potency with that of imatinib. It potently inhibited Bcr-AblWT and Bcr-AblT315I kinases with IC50 of 0.043 µM and 0.17 µM, respectively. Furthermore, compound Y9 inhibited the proliferation of K562 and K562R cells with IC50 of 1.65 µM and 5.42 µM, respectively. Therefore, 6-phenyl-1H-indazol-3amine as HBM, combined with flexible linker, is a successful strategy contribute to research on T315I mutant resistance, and compound Y9 could be served as a starting point for further optimization.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Benzamidas/síntese química , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Simulação de Acoplamento Molecular , Mutação , Piperazinas/síntese química , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Maleabilidade , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo
3.
Phys Chem Chem Phys ; 21(27): 15120-15132, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31241637

RESUMO

The concept of chirality has become prominent over the years, particularly with regards to the design of therapeutic molecules. This phenomenon was recently reported for pro-carcinogenic fibroblast growth factor receptor 1 (FGFR1), wherein two inhibitors exhibited disparate inhibitory potencies due to the effects of chirality. Therefore, the ability of the R-enantiomer (R-21c) to possess a potency 10.44 times that of the S-enantiomer (S-21c) leaves us with a curiosity to investigate the underlying mechanisms using computational methods. Hence, presented in this study are insights that clearly explain the systematic effects of chirality on the differential activities of (R)-21c and (S)-21c towards FGFR1. The findings showed that the "R-configured" (R)-21c induced a notable conformational change in the active site P-loop, which enhanced its motion, as complemented by rotation of two dihedral angles: φ1(CNCC) and φ2(CC*OC), providing a favorable orientation. Likewise, optimal positioning of (R)-21c at the binding cavity allowed adequate interspaces that facilitated the formation of strong interactions with target residues. Moreover, the estimated ΔG binding correlated with bioactivity data (IC50) and, when decomposed, we observed that van der Waals (vdW) interactions were the major highlight of the binding process of both 21c enantiomers and also accounted for their differential activities. Active site interactions of (R)-21c with residues Phe489 and Arg629 stabilized its two benzimidazole motifs, while Arg570 and Pro663 formed two strong NH-N hydrogen bonds and one π-alkyl interaction, which altogether accounted for its inhibitory prowess towards FGFR1. In contrast, these interactions were not observed in (S)-21c due to its non-flexible S-configuration, which disallowed its extension into the active site region and prevented interaction with crucial residues. These results are expected to facilitate the discovery and rational design of novel and specific FGFR1 inhibitors.


Assuntos
Indazóis/química , Indazóis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Concentração Inibidora 50 , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia
4.
Nat Commun ; 10(1): 2427, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160593

RESUMO

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.


Assuntos
Colite/imunologia , Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Doenças Inflamatórias Intestinais/imunologia , Células Supressoras Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/etiologia , Sulfato de Dextrana/toxicidade , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Hematopoéticas/citologia , Código das Histonas , Histonas/metabolismo , Técnicas In Vitro , Indazóis/farmacologia , Indóis/farmacologia , Metilação , Camundongos , Células Supressoras Mieloides/citologia , Piridonas/farmacologia
5.
Nat Commun ; 10(1): 2205, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101821

RESUMO

Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Indazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/secundário , Carcinogênese/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/secundário , Linhagem Celular Tumoral , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Feminino , Humanos , Indazóis/uso terapêutico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Biomolecules ; 9(3)2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30813656

RESUMO

Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.


Assuntos
Indazóis/química , Indazóis/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Química Farmacêutica , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Relação Estrutura-Atividade
7.
Reprod Domest Anim ; 54(5): 741-749, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30785650

RESUMO

Steroid hormones are required for normal reproductive function of female. The aim of this study was to investigate the role of Raf-ERK1/2 on steroid hormone synthesis in bovine ovarian granulosa cells. Immunohistochemistry assay showed that both B-Raf and C-Raf were expressed in granulosa cells, theca cells and Sertoli cells. The protein expression of Raf or ERK1/2 was clearly decreased by Raf inhibitor GSK2118436 or ERK1/2 inhibitor SCH772984, respectively (p < 0.05). In addition, western blotting was performed for investigating the crosstalk between Raf and ERK1/2, the data showed that Raf positively regulated ERK1/2, whereas ERK1/2 had a negative feedback effect on Raf. The biosynthesis of oestradiol or testosterone was significantly decreased by treatment with GSK2118436 or SCH772984 (p < 0.05). Conversely, the progesterone biosynthesis was clearly increased by treatment with those inhibitors (p < 0.05). Furthermore, the mRNA expression of STAR, aromatase and CYP17 was blocked by Raf-ERK1/2 signalling inhibition, which oppositely induced the mRNA expression of CYP11. Together, these findings suggested that Raf-ERK1/2 signalling pathways mediate steroid hormone synthesis via affecting the expression of steroidogenic enzymes.


Assuntos
Estradiol/biossíntese , Células da Granulosa/metabolismo , Sistema de Sinalização das MAP Quinases , Progesterona/biossíntese , Testosterona/biossíntese , Animais , Bovinos , Células Cultivadas , Feminino , Expressão Gênica , Células da Granulosa/efeitos dos fármacos , Imidazóis/farmacologia , Indazóis/farmacologia , Oximas/farmacologia , Piperazinas/farmacologia , RNA Mensageiro/genética
8.
Chem Biodivers ; 16(5): e1800598, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788913

RESUMO

Human nasopharyngeal carcinoma is a common head and neck malignancy with high incidence in Southeast Asia and Southern China. It is necessary to develop safe, effective and inexpensive anticancer agents to improve the therapeutics of patients with nasopharyngeal carcinoma. A series of small molecular compounds based on 6-(pyrimidin-4-yl)-1H-indazole were synthesized and evaluated for antiproliferative activities against human nasopharyngeal carcinoma cell lines SUNE1. Compounds 6b, 6c, 6e and 6l showed potent antiproliferative activities similar to positive control drug cisplatin in vitro with lower nephrotoxicity than it. N-[4-(1H-Indazol-6-yl)pyrimidin-2-yl]benzene-1,3-diamine (6l) was selected for further study. It was found that 6l induced mitochondria-mediated apoptosis and G2 /M phase arrest in SUNE1 cells. Furthermore, compound 6l at 10 mg/kg can suppress the growth of an implanted SUNE1 xenograft with a TGI% (tumor growth inhibition) value of 50 % and did not cause serious side effects in BALB/c nude mice. This study suggests that 6-(pyrimidin-4-yl)-1H-indazole derivatives are a series of small molecule compounds with anti-nasopharyngeal carcinoma activities.


Assuntos
Antineoplásicos/síntese química , Indazóis/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Relação Estrutura-Atividade , Transplante Heterólogo
9.
Life Sci ; 222: 117-124, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30708100

RESUMO

Obesity is caused by energy imbalance and accompanied by adipocyte hypertrophy and hyperplasia. Therefore, both enhancement of adipocyte energy expenditure and inhibition of adipogenesis are viable ways to combat obesity. Using the Ucp1-2A-luciferase reporter animal model previously reported by us as a screening platform, a chemical compound Linifanib was identified as a potent inducer of UCP1 expression in primary inguinal adipocytes in vitro and in vivo. Signal pathway analyses showed that Linifanib promoted adipocyte browning by attenuating STAT3 phosphorylation. The effects of Linifanib on adipocyte browning were blocked by the compound, SD19, which activates the STAT3 signaling cascade. Linifanib also inhibited adipocyte differentiation, by blocking mitotic clonal expansion, which could be rescued by STAT3 activator. Taken together, our results indicate that Linifanib might serve as a potential drug for the treatment of obesity.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Indazóis/farmacologia , Compostos de Fenilureia/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Células 3T3-L1 , Adipócitos Marrons/metabolismo , Adipogenia/fisiologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Camundongos , Camundongos Transgênicos , Distribuição Aleatória , Fator de Transcrição STAT3/metabolismo , Smegmamorpha
10.
Epigenetics ; 14(1): 94-108, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30661456

RESUMO

Enhancer of zeste homolog 2 (EZH2), a component of the PRC2 complex, trimethylates H3K27, a transcriptionally repressive histone mark. EZH2 is encoded by a dormant maternal mRNA and inhibiting the maturation-associated increase in EZH2 activity using either a combined siRNA/morpholino approach or a small molecule inhibitor (GSK343) inhibits development of diploidized parthenotes to the blastocyst stage but not inseminated eggs, with longer GSK343 treatments leading to progressively greater inhibition of development. GSK343 treatment also results in a decrease in H3K27me3 and a decrease in global transcription in 2-cell parthenotes but not 2-cell embryos derived from inseminated eggs. RNA-sequencing revealed the relative abundance of ~100 zygotically-expressed transcripts is decreased by GSK treatment in parthenotes, but not in embryos, with many of the affected transcripts encoding proteins involved in transcription. A previous study found that parthenotes deficient in maternal Ezh2 readily develop to the blastocyst stage. To reconcile these differences we propose that the H3K27me3 state present in the zygote needs to be faithfully propagated following DNA replication in at least one pronucleus, otherwise development is compromised.


Assuntos
Blastocisto/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Herança Paterna , Animais , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Histonas/genética , Histonas/metabolismo , Indazóis/farmacologia , Masculino , Camundongos , Piridonas/farmacologia , Transcriptoma
11.
Bull Exp Biol Med ; 166(3): 310-312, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627906

RESUMO

Application of mild irritants (1 M NaCl; pH 2.0) on the gastric mucosa potentiates the protective secretion of bicarbonates by epithelial cells. This response is mainly mediated by capsaicin-sensitive afferent nerve endings located in the submucosa. It was shown that activation of vanilloid type 1 receptors (TRPV1) induced by exogenous acidification of GM is not sufficient to potentiate the production of HCO3, including production depending on neuronal NO synthase. However, the effect of exogenous acid on TRPV1 leads to activation of endothelial NO synthase that restrict the gastric secretion of [Formula: see text].


Assuntos
Bicarbonatos/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo I/genética , Cloreto de Sódio/farmacologia , Estômago/efeitos dos fármacos , Canais de Cátion TRPV/genética , Amilorida/farmacologia , Animais , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Mucosa Gástrica/inervação , Mucosa Gástrica/metabolismo , Regulação da Expressão Gênica , Concentração de Íons de Hidrogênio , Indazóis/farmacologia , Masculino , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroarginina/farmacologia , Concentração Osmolar , Perfusão , Nervo Frênico/cirurgia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Estômago/inervação , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Vagotomia
12.
J Mol Neurosci ; 67(3): 477-483, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30627955

RESUMO

Preconditioning is defined as an induction of adaptive response in organs against lethal stimulation provoked by subsequent mild sublethal stress. Several chemical agents have been demonstrated to cause brain tolerance through preconditioning. The aim of the present study is to test the hypothesis that preconditioning with pentylenetetrazole (PTZ) may have protective effect against seizure induced by i.v. infusion of PTZ. Mice were preconditioned by low-dose administration of PTZ (25 mg/kg) for 5 consecutive days, and the threshold of seizure elicited by i.v. infusion of PTZ was measured. To investigate the possible role of nitric oxide, NOS inhibitor enzymes, including L-NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) (10 mg/kg), aminoguanidine (AG) (50 mg/kg), 7-nitroindazole (7-NI) (15 mg/kg), and L-arginine (L-arg) (60 mg/kg), were administered concomitantly with PTZ in both acute and chronic phases. Determination of seizure threshold revealed significant enhancement after preconditioning with low dose of PTZ. While the protective effect of PTZ preconditioning was enhanced after the administration of L-arg, it was reversed following administration of L-NAME and 7NI, suggesting the involvement of nitric oxide pathway as an underlying mechanism of PTZ-induced preconditioning. Preconditioning with PTZ led to brain tolerance and adaptive response in animal model of PTZ-induced seizure. This effect is in part due to the involvement of nitric oxide pathway.


Assuntos
Antagonistas GABAérgicos/uso terapêutico , Óxido Nítrico/metabolismo , Pentilenotetrazol/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Antagonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/farmacologia , Guanidinas/farmacologia , Indazóis/farmacologia , Masculino , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Pentilenotetrazol/administração & dosagem , Pentilenotetrazol/farmacologia , Transdução de Sinais
13.
Int J Mol Sci ; 20(2)2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634531

RESUMO

Tissue factor (TF) expressed in cancer cells has been linked to tumor-associated thrombosis, a major cause of mortality in malignancy. Hypoxia is a common feature of solid tumors and can upregulate TF. In this study, the effect of YC-1, a putative inhibitor of hypoxia-inducible factor-1α (HIF-1α), on hypoxia-induced TF expression was investigated in human lung cancer A549 cells. YC-1 selectively prevented hypoxia-induced TF expression and procoagulant activity without affecting the basal TF levels. Surprisingly, knockdown or pharmacological inhibition of HIF-1α failed to mimic YC-1's effect on TF expression, suggesting other mechanisms are involved. NF-κB, a transcription factor for TF, and its upstream regulator p38, were activated by hypoxia exposure. Treatment of hypoxic A549 cells with YC-1 prevented the activation of both NF-κB and p38. Inhibition of p38 suppressed hypoxia-activated NF-κB, and inhibited TF expression and activity to similar levels as treatment with an NF-κB inhibitor. Furthermore, stimulation of p38 by anisomycin reversed the effects of YC-1. Taken together, our results suggest that YC-1 prevents hypoxia-induced TF in cancer cells by inhibiting the p38/NF-κB pathway, this is distinct from the conventional anticoagulants that systemically inhibit blood coagulation and may shed new light on approaches to treat tumor-associated thrombosis.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Indazóis/farmacologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tromboplastina/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Plaquetas/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas Quinases Reguladas por Nucleotídeo Cíclico/metabolismo , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
14.
Bioorg Med Chem Lett ; 29(2): 155-159, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30538066

RESUMO

The transient receptor potential cation channel 5 (TRPC5) has been previously shown to affect podocyte survival in the kidney. As such, inhibitors of TRPC5 are interesting candidates for the treatment of chronic kidney disease (CKD). Herein, we report the synthesis and biological characterization of a series of N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors. Work reported here evaluates the benzimidazole scaffold and substituents resulting in the discovery of AC1903, a TRPC5 inhibitor that is active in multiple animal models of CKD.


Assuntos
Aminas/farmacologia , Compostos Heterocíclicos/farmacologia , Imidazóis/farmacologia , Indazóis/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Canais de Cátion TRPC/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Drogas , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Imidazóis/síntese química , Imidazóis/química , Indazóis/síntese química , Indazóis/química , Estrutura Molecular , Insuficiência Renal Crônica/metabolismo , Relação Estrutura-Atividade , Canais de Cátion TRPC/síntese química , Canais de Cátion TRPC/química , Canais de Cátion TRPC/metabolismo , Canais de Cátion TRPC/farmacologia
15.
Cancer Lett ; 443: 91-107, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30529153

RESUMO

Despite the clinical success of temozolomide (TMZ), its sensitivity remains a major challenge in glioblastoma (GBM). Here, we show that PLK4 affects TMZ sensitivity by regulating the IKBKE/NF-κB axis. The mRNA level of PLK4 was significantly associated with glioma grade progression and inversely correlated with overall survival (OS) in patients with high-grade gliomas (HGG). Further analyses indicated that GBM patients with low PLK4 expression levels gained greater survival benefits from chemotherapy than did those with high PLK4 expression. In GBM cells, TMZ sensitivity was decreased by ectopic expression of PLK4 and enhanced by depletion of PLK4. In the GBM mice model, inhibiting PLK4 in combination with chemotherapy slowed tumor growth and provided a significant survival benefit. Furthermore, PLK4 interacted with and phosphorylated IKBKE, leading to an increase in NF-κB transcriptional activity and anti-apoptosis. Notably, the PLK4 inhibitor CFI400945, which is currently in clinical trials, had a synergistic effect with TMZ, increasing TMZ sensitivity in xenografts from patient-derived primary GBMs. Our work describes the PLK4-IKBKE signaling axis that influences GBM proliferation and chemosensitivity, and can enhance the anti-tumor effects of chemotherapy via therapeutic targeting.


Assuntos
Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/patologia , Quinase I-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Adolescente , Adulto , Idoso , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Criança , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Indazóis/administração & dosagem , Indazóis/farmacologia , Indóis/administração & dosagem , Indóis/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação , Prognóstico , Análise de Sobrevida , Temozolomida/administração & dosagem , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
16.
Biomed Pharmacother ; 109: 1867-1875, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551442

RESUMO

Hypertension crisis is a severe disease and needs emergency treatment in clinic. It is an important task to discover novel drugs which could lower the blood pressure steadily and quickly. However, animal models for screening anti-hypertensive crisis agents are unsatisfactory. The present study aimed to establish a new hypertensive crisis rat model and then explore the therapeutic effects of three Rho-kinase inhibitors including Fasudil, DL0805-1 and DL0805-2 on such a disease model. The hypertensive crisis symptoms were developed on male Wistar rats by subcutaneously injecting small doses of norepinephrine (NE) for 10 days in the initial stage. A sudden increase in blood pressure (BP) was then induced by excessive NE infusion. Compounds to be tested were intravenously injected into the rats immediately when the rapidly increased systolic blood pressure appeared. The results have shown that after small dose administration with NE, the rats could obtain acute BP increase to a high level without sudden death when a large dose of NE was injected. Fasudil, DL0805-1 and DL0805-2 could lower the blood pressure quickly in a dose dependent manner and improve the survival rate. The compounds also prevent the animals from organ damage. In conclusion, we established a novel hypertensive crisis animal model which could evaluate agents within a short time. In this model, we found that three Rho-kinase inhibitors have potential therapeutic effects on hypertensive crisis. This work might contribute to the discovery and development of new anti-hypertensive crisis drugs.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Norepinefrina/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Indazóis/farmacologia , Masculino , Nitrilos/farmacologia , Ratos , Ratos Wistar
17.
Eur J Med Chem ; 163: 671-689, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30572178

RESUMO

Although lung adenocarcinoma patients have benefited from the development of targeted therapy, patients with lung squamous cell carcinoma (SqCC) have no effective treatment due to the complexity and heterogeneity of the disease. Therefore, basing on the genetic analysis of mutations in lung squamous cell carcinoma to design multi-target inhibitors represents a potential strategy for the medical treatment. In this study, through screening an in-house focused library, we identified an interesting indazole scaffold. And following with binding analysis, we elaborated the structure-activity relationship of this hit compound by optimizing four parts guided by the DDR2 enzymatic assay, which resulted in a potent lead compound 10a. We conducted further optimization of dual enzymatic inhibitions towards FGFR1 and DDR2, two important kinases in lung squamous cell carcinoma. Finally, from the cellular antiproliferative activity tests and in vivo pharmacokinetic test, 3-substituted indazole derivative 11k was found to be a promising candidate and subjected to in vivo pharmacology study with the mouse xenograft models, demonstrating profound anti-tumor efficacy. Additional in vitro druglike assessment reinforced that compound 11k could be valuable for SqCC drug development.


Assuntos
Antineoplásicos/síntese química , Carcinoma de Células Escamosas/tratamento farmacológico , Descoberta de Drogas , Indazóis/síntese química , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Animais , Carcinoma de Células Escamosas/enzimologia , Receptor com Domínio Discoidina 2/antagonistas & inibidores , Xenoenxertos , Humanos , Indazóis/química , Indazóis/farmacologia , Neoplasias Pulmonares/enzimologia , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Relação Estrutura-Atividade
18.
J Steroid Biochem Mol Biol ; 185: 27-38, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30009951

RESUMO

SIRT2 has been shown to possess NAD+-dependent deacetylase and desuccinylase enzymatic activities, it also regulates metabolism homeostasis in mammals. Previous data has suggested that resveratrol, a potential activator of Sirtuins, played a stimulation role in steroidogenesis. Unfortunately, to date, the physiological roles of SIRT2 in ovarian granular cells (GCs) are largely unknown. Here, we studied the function and molecular mechanisms of SIRT2 on steroid hormone synthesis in GCs from Qinchuan cattle. Immunohistochemistry and western blotting showed that SIRT2 was expressed not only in GCs and cumulus cells, but also in oocytes and theca cells. We found that the secretion of progesterone was induced, whereas that of estrogen and testosterone secretion was suppressed by treatment with the SIRT2 inhibitor (Thiomyristoyl or SirReal2) or siRNA. Additionally, the PPARs/LXRα signaling pathways were suppressed by SIRT2 siRNA or inhibitors. The mRNA expression of CYP17, aromatase and StAR was suppressed, but the abundance of CYP11A1 mRNA was induced by SIRT2 inhibition. Furthermore, the PPARα agonist or PPARγ antagonist could mimic the effects of SIRT2 inhibition on hormones levels and gene expression associated with steroid hormone biosynthesis. In turn, those effects were abolished by the LXRα agonist (LXR-623). Together, these data support the hypothesis that SIRT2 regulates steroid hormone synthesis via the PPARs/LXRα pathways in GCs.


Assuntos
Estradiol/biossíntese , Células da Granulosa/metabolismo , Receptores X do Fígado/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Progesterona/biossíntese , Sirtuína 2/metabolismo , Testosterona/biossíntese , Acetamidas/farmacologia , Animais , Bovinos , Células Cultivadas , Enzima de Clivagem da Cadeia Lateral do Colesterol/biossíntese , Feminino , Indazóis/farmacologia , Receptores X do Fígado/agonistas , Oócitos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/genética , Esteroide 17-alfa-Hidroxilase/biossíntese , Células Tecais/metabolismo , Tiazóis/farmacologia
19.
Lung Cancer ; 126: 32-40, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527190

RESUMO

PURPOSE: Metabolic inhibition might sensitize tumors to irradiation. Here, we examined the effect of lonidamine (several metabolic effects, inhibiting hexokinase amongst others) and/or 968 (glutaminase inhibitor) on tumor cell metabolism, cell growth, cytotoxicity and radiosensitivity in NSCLC cell lines in vitro in relation to histology. MATERIALS AND METHODS: Adeno- (H23, HCC827, H1975) and squamous cell carcinoma (H520, H292, SW900) NSCLC cells were treated with lonidamine and/or 968 for 72 h under physiological levels of glucose (1.5 mM). Cells were irradiated with 0, 4 or 8 Gy. Cell growth of H2B-mCherry transduced cells and cytotoxicity (CellTox™ Green Cytotoxicity Assay) were measured using live cell imaging (IncuCyte). Inhibitory effects on metabolic profiles was determined using the Seahorse XF96 extracellular Flux analyzer. RESULTS: NSCLC cell lines responded differently to glycolysis (lonidamine) and/or glutaminase (968) inhibition, largely corresponding with changes in glycolytic and mitochondrial metabolism upon treatment. Response patterns were not related to histology. 968 was cytotoxic in cell lines with high glutaminase C expression (H1975 and H520), whereas combination treatment was cytotoxic in KRAS mutated cell lines SW900 and H23. H292 and HCC827 were resistant to combination treatment. Treatment with 968 and especially lonidamine resulted in radiosensitization of H292 and HCC827 in terms of decreased relative cell growth and increased cytotoxicity. CONCLUSION: NSCLC is a heterogeneous disease, which is reflected in the response of different cell lines to the treatment (combinations) reported here. Only a part of NSCLC patients may benefit from the combination of radiation therapy and metabolic inhibition, making stratification necessary.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Glutamina/metabolismo , Indazóis/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Relação Dose-Resposta à Radiação , Glutaminase/antagonistas & inibidores , Glutaminase/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/efeitos da radiação , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Raios X
20.
Cancer Cell ; 34(6): 922-938.e7, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30537514

RESUMO

Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.


Assuntos
Azepinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indazóis/farmacologia , Terapia de Alvo Molecular/métodos , Neuroblastoma/tratamento farmacológico , Sulfonamidas/farmacologia , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Intervalo Livre de Doença , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Camundongos Nus , Neuroblastoma/genética , Neuroblastoma/metabolismo , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos
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