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1.
J Med Chem ; 64(20): 15170-15188, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34664960

RESUMO

The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been identified in hematologic malignancies and solid tumors. Based on the structure of EPZ6438 (1) and the binding model with PRC2, we designed a series of analogues aiming to improve the activities of EZH2 mutants. Structure-activity relationship (SAR) exploration at both enzymatic and cellular levels led to the discovery of inhibitor 29. In the biochemical assay, 29 inhibited EZH2 (IC50 = 26.1 nM) with high selectivity over other histone methyltransferases. It was also potent against EZH2 mutants (EZH2 Y641F, IC50 = 72.3 nM). Furthermore, it showed no apparent inhibitory activity against the human ether-á-go-go related gene (hERG) (IC50 > 30 µM). In vivo, 29 exhibited favorable pharmacokinetic properties for oral administration and showed better efficacy than 1 in both Pfeiffer and Karpas-422 cell-mediated xenograft mouse models, indicating that it might be a new potential therapeutic candidate for EZH2 mutant cancers.

3.
J BioX Res ; 4(2): 53-59, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34254034

RESUMO

Objective: Emetine, an isoquinoline alkaloid that is enriched at high concentrations in the lung, has shown potent in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to better understand the effectiveness of low-dose emetine for patients with coronavirus disease 2019 (COVID-19). Methods: In this real-world study, 63 patients with mild or common COVID-19 were recruited from Wuhan Fangcang Shelter Hospital and five COVID-19-designated hospitals in Anhui Province, China from February to March 2020. Thirty-nine patients from Wuhan Fangcang Shelter Hospital were assigned to a pragmatic randomized controlled clinical trial, and 24 patients from the 5 COVID-19-designated hospitals in Anhui Province underwent a real-world study. The medication course of emetine was less than 10 days. The main symptoms and adverse reactions of all patients were observed and recorded. The primary outcome measure was the time required for a negative SARS-CoV-2 RNA result or the negative result rate on day 10. Secondary outcomes included axillary temperature, transcutaneous oxygen saturation, and respiratory frequency recovery. The study was approved by the Ethics Committee of The First Affiliated Hospital of Anhui Medical University on February 20, 2019 (approval No. PJ2020-03-19) and was registered with the Chinese Clinical Trial Registry on February 20, 2019 (registration number: ChiCTR2000030022). Results: The oxygen saturation values were higher in the treatment group than in the control group on the first day after enrollment for patients treated at Fangcang Shelter Hospital. The axillary body temperature, respiratory rate, and oxygen saturation among patients in Fangcang Shelter Hospital were related to the time effect but not to the intervention measures. The respiratory rate and oxygen saturation of patients in the Anhui designated hospitals were related to the intervention measures but not to the time effect. The axillary body temperature of patients in Anhui designated hospitals was related to the time effect but not to the intervention measures. Conclusion: Our preliminary study shows that low-dose emetine combined with basic conventional antiviral drugs improves clinical symptoms in patients with mild and common COVID-19 without apparent adverse effects, suggesting that moderately increased doses of emetine may have good potential for treatment and prevention of COVID-19.

4.
Front Physiol ; 12: 646721, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815150

RESUMO

The wide-spread culture of transgenic Bt cotton resisting the infamous cotton bollworms has reduced the adoption of broad-spectrum insecticides to a large extent. Consequently, the non-targeted insect Adelphocoris suturalis Jakovlev has become a major cotton pest in China. Entomopathogenic microbes show promising results for controlling this pest in the future, but A. suturalis innate immune responses to these pathogens are poorly understood. Here, we used the entomopathogenic fungus Beauveria bassiana and the Gram-negative pathogenic bacteria Enterobactor cloacae to infect A. suturalis nymphs, followed by high throughput RNA-seq to analyze the immune transcriptomes of A. suturalis in response to the two pathogens. A total of 150 immunity-related genes were identified, including pattern recognition receptors, extracellular signal modulators, signal pathways (Toll, IMD, JNK, and JAK/STAT), and response effectors. Further quantitative real-time PCR analysis demonstrated that B. bassiana and E. cloacae were recognized by different receptors (GNBP and PGRP, respectively); activated Toll pathway and IMD pathway respectively; and both induced expression of the effector gene Defensin. However, melanization is suppressed in B. bassiana-infected nymphs. Collectively, this study provides a transcriptomic snapshot of the A. suturalis immune system, and at the genetic level, gains multifaceted insights of the immune response to fungal and Gram-negative bacterial pathogens. Ultimately this work pioneers the study of molecular mechanisms underlying immune interactions between A. suturalis and its pathogens and assists in the development of novel mitigation strategies to control this pest.

5.
Sci Total Environ ; 771: 144880, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33736123

RESUMO

Diet is an important factor in shaping and influencing both an insect's phenotype and gut bacterial community, which commonly establishes diversely symbiotic interactions with the host. Efforts to leverage the connection between diet, insects, and gut microbiome primarily focus on how diet alters insect's phenotype or gut microbial composition and relatively few studies have illuminated the link between the diet-induced insect phenotypic difference and variation of gut microbiota. Mirids bugs, Adelphocoris suturalis, are plant sap-feeding omnivores that sometimes complementarily prey on other insects, like aphids (the dietary regime is referred to hereafter as balanced diet). In this study, we found that an imbalanced diet (exclusive ingestion of aphids) induced significantly higher mortality in A. suturalis (86.66%). Further gut microbial community analysis showed that the dietary difference significantly changed both the abundance and composition of the bug's gut microbiome. Most notably, an abundance of entomopathogenic Serratia bacteria in the A. suturalis gut was positively correlated with the proportion of aphids in A. suturalis diet, and Serratia marcescens was found to transfer into the hemocoels of carnivorous bugs. Injection of S. marcescens to the hemocoels further confirmed its detrimental effect to the bugs. Collectively, our study suggests that the diet-altered variation of gut microbiota may be detrimental to host insect, advancing the knowledge of omnivorous insects' strategy in forage allocation of different foods.


Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Bactérias/genética , Dieta , RNA Ribossômico 16S
6.
Eur J Pharmacol ; 897: 173944, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581133

RESUMO

As the critical driving force for chronic myeloid leukemia (CML), BCR gene fused ABL kinase has been extensively explored as a validated target of drug discovery. Although imatinib has achieved tremendous success as the first-line treatment for CML, the long-term application ultimately leads to resistance, primarily via various acquired mutations occurring in the BCR-ABL kinase. Although dasatinib and nilotinib have been approved as second-line therapies that could overcome some of these mutants, the most prevalent gatekeeper T315I mutant remains unconquered. Here, we report a novel type II kinase inhibitor, CHMFL-48, that potently inhibits the wild-type BCR-ABL (wt) kinase as well as a panel of imatinib-resistant mutants, including T315I, F317L, E255K, Y253F, and M351T. CHMFL-48 displayed great inhibitory activity against ABL wt (IC50: 1 nM, 70-fold better than imatinib) and the ABL T315I mutant (IC50: 0.8 nM, over 10,000-fold better than imatinib) in a biochemical assay and potently blocked the autophosphorylation of BCR-ABL wt and BCR-ABL mutants in a cellular context, which further affected downstream signalling mediators, including signal transducer and activator of transcription 5 (STAT5) and CRK like proto-oncogene (CRKL), and led to the cell cycle progression blockage as well as apoptosis induction. CHMFL-48 also exhibited great anti-leukemic efficacies in vivo in K562 cells and p210-T315I-transformed BaF3 cell-inoculated murine models. This discovery extended the pharmacological diversity of BCR-ABL kinase inhibitors and provided more potential options for anti-CML therapies.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Fusão Gênica , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Nus , Mutação , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Cell Physiol ; 236(8): 5921-5936, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33481281

RESUMO

Plant bugs (Miridae species) have become major agricultural pests that cause increasing and severe economic damage. Plant-mediated RNA interference (RNAi) is emerging as an eco-friendly, efficient, and reliable strategy for pest management. In this study, we isolated and characterized a lethal gene of Apolygus lucorum and named it Apolygus lucorum LIM (AlLIM), which produced A. lucorum mortality rates ranging from 38% to 81%. Downregulation of the AlLIM gene expression in A. lucorum by injection of a double-stranded RNA (dsRNA) led to muscle structural disorganization that resulted in metamorphosis deficiency and increased mortality. Then we constructed a plant expression vector that enabled transgenic cotton to highly and stably express dsRNA of AlLIM (dsAlLIM) by Agrobacterium-mediated genetic transformation. In the field bioassay, dsAlLIM transgenic cotton was protected from A. lucorum damage with high efficiency, with almost no detectable yield loss. Therefore, our study successfully provides a promising genetically modified strategy to overpower A. lucorum attack.


Assuntos
Gossypium/parasitologia , Heterópteros/genética , Insetos/genética , Interferência de RNA/imunologia , Animais , Plantas/parasitologia
8.
Acta Pharmacol Sin ; 42(4): 633-640, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32737469

RESUMO

Inhibition of glycolysis process has been an attractive approach for cancer treatment due to the evidence that tumor cells are more dependent on glycolysis rather than oxidative phosphorylation pathway. Preliminary evidence shows that inhibition of phosphoglycerate kinase 1 (PGK1) kinase activity would reverse the Warburg effect and make tumor cells lose the metabolic advantage for fueling the proliferation through restoration of the pyruvate dehydrogenase (PDH) activity and subsequently promotion of pyruvic acid to enter the Krebs cycle in glioma. However, due to the lack of small molecule inhibitors of PGK1 kinase activity to treat glioma, whether PGK1 could be a therapeutic target of glioma has not been pharmacologically verified yet. In this study we developed a high-throughput screening and discovered that NG52, previously known as a yeast cell cycle-regulating kinase inhibitor, could inhibit the kinase activity of PGK1 (the IC50 = 2.5 ± 0.2 µM). We showed that NG52 dose-dependently inhibited the proliferation of glioma U87 and U251 cell lines with IC50 values of 7.8 ± 1.1 and 5.2 ± 0.2 µM, respectively, meanwhile it potently inhibited the proliferation of primary glioma cells. We further revealed that NG52 (12.5-50 µM) effectively inhibited the phosphorylation of PDHK1 at Thr338 site and the phosphorylation of PDH at Ser293 site in U87 and U251 cells, resulting in more pyruvic acid entering the Krebs cycle with increased production of ATP and ROS. Therefore, NG52 could reverse the Warburg effect by inhibiting PGK1 kinase activity, and switched cellular glucose metabolism from anaerobic mode to aerobic mode. In nude mice bearing patient-derived glioma xenograft, oral administration of NG52 (50, 100, 150 mg· kg-1·d-1, for 13 days) dose-dependently suppressed the growth of glioma xenograft. Together, our results demonstrate that targeting PGK1 kinase activity might be a potential strategy for glioma treatment.


Assuntos
Adenina/análogos & derivados , Adenina/uso terapêutico , Glioma/tratamento farmacológico , Fosfoglicerato Quinase/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Glioma/enzimologia , Humanos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Efeito Warburg em Oncologia/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Acta Pharmacol Sin ; 42(1): 108-114, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32398685

RESUMO

Glioblastoma (GBM) patients have extremely poor prognoses, and currently no effective treatment available including surgery, radiation, and chemotherapy. MAPK-interacting kinases (MNK1/2) as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells. Research has shown that targeting MNKs may be an effective strategy to treat GBM. In this study we investigated the antitumor activity of osimertinib, an FDA-approved epidermal growth factor receptor (EGFR) inhibitor, against patient-derived primary GBM cells. Using high-throughput screening approach, we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients, found that osimertinib (3 µM) suppressed the proliferation of a subset (10/22) of EGFR-negative GBM cells (>50% growth inhibition). We detected the gene expression difference between osimertinib-sensitive and -resistant cells, found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway. We further showed that osimertinib potently inhibited the MNK kinase activities with IC50 values of 324 nM and 48.6 nM, respectively, against MNK1 and MNK2 kinases; osimertinib (0.3-3 µM) dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). In GBM patient-derived xenografts mice, oral administration of osimertinib (40 mg· kg-1 ·d-1, for 18 days) significantly suppressed the tumor growth (TGI = 74.5%) and inhibited eIF4E phosphorylation in tumor cells. Given the fact that osimertinib could cross the blood-brain barrier and its toxicity was well tolerated in patients, our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Criança , Receptores ErbB/deficiência , Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
11.
J Med Chem ; 63(22): 13973-13993, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33180507

RESUMO

Accumulated pieces of evidence have shown that PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδ inhibitor (S)-18. In the biochemical assay, (S)-18 inhibits PI3Kδ (IC50 = 14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). (S)-18 also achieves good selectivity over other protein kinases in the kinome (S-score (35) = 0.015). In the cell, (S)-18 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, (S)-18 exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC50 > 10 µM). In vivo, (S)-18 displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that (S)-18 might be a new potential therapeutic candidate for COPD.


Assuntos
Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 207: 112744, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949955

RESUMO

Due to the critical tumorigenic role of fused NTRK genes in multiple cancers, TRK kinases have attracted extensive attention as a drug discovery target. Starting from an indazole based scaffold, through the type II kinase inhibitor fragments hybrid design approach with a ring closure strategy, we discovered a novel potent type II TRK kinase inhibitor compound 34 (IHMT-TRK-284), which exhibited IC50 values of 10.5 nM, 0.7 nM and 2.6 nM to TRKA, B, and C respectively. In addition, it displayed great selectivity profile in the kinome when tested among 468 kinases and mutants (S score (1) = 0.02 at 1 µM). Importantly, 34 could overcome drug resistant mutants including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region. In vivo, 34 exhibited good PK profiles in different species including mice, rats, and dogs. It also displayed good in vivo antitumor efficacies in the TRKA/B/C, TRKA mutants, and KM-12-LUC cells mediated mouse models. The potent activity against clinically important TRK mutants combined with the good in vivo PK and efficacy properties of 34 indicated that it might be a new potential therapeutic candidate for TRK kinase fusion or mutants driven cancers.


Assuntos
Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mutação , Receptor trkA/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cães , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos , Receptor trkA/genética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Exp Cell Res ; 393(1): 112054, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32376287

RESUMO

Acute myeloid leukemia (AML) is one of the most common, complex, and heterogeneous hematological malignancies in adults. Despite progresses in understanding the pathology of AML, the 5-year survival rates still remain low compared with CML, CLL, etc. The relationship between genomic features and drug responses is critical for precision medication. Herein, we depicted a picture for response of 145 drugs against 33 primary cell samples derived from AML patients with full spectrum of genomic features assessed by whole exon sequencing and RNA sequencing. In general, most of the samples were much more sensitive to the combinatorial chemotherapy regimens than the single chemotherapy drugs. Overall, these samples were moderately sensitive to the Traditional Chinese Medicine (TCM) and the targeted drugs. In the weighted gene coexpression network analysis (WGCNA), the TCM and targeted therapies displayed similar genetic signatures in the gene module correlation. Meanwhile, the expression of miRNAs, lncRNAs, and mRNAs did not display apparent gene module correlations among those different types of therapies. In addition, the combinatorial chemotherapy bear more module correlations than the single drugs. Interestingly, we found that the gene mutations and drug response were not enriched in any WGCNA module analysis. Most of the sensitive drug response biomarkers were enriched in the ribosome, endocytosis, cell cycle, and p53 associated signaling pathways. This study showed that gene expression modules might show better correlation than gene mutations for drug efficacy predictions.


Assuntos
Biomarcadores Tumorais/análise , Redes Reguladoras de Genes/genética , Leucemia Mieloide Aguda/genética , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Mutação/genética , Preparações Farmacêuticas/metabolismo , RNA Mensageiro/genética
15.
Acta Pharm Sin B ; 10(3): 488-497, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32140394

RESUMO

Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC50 = 66 nmol/L) and VEGFR2 autophosphorylation in cells (EC50s ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI50 = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.

16.
Cancer Lett ; 473: 130-138, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31904486

RESUMO

All-trans retinoic acid (ATRA) is known to be a potent inhibitor of FLT3-ITD acute myeloid leukemia (AML) cells, although the exact mechanism remains unclear. In this work, we report that ATRA causes fatal mitotic catastrophe in FLT3-ITD AML cells by degrading Chk1 kinase, and therefore preventing DNA damage repair. In order to explore a further enhancement in the inhibitory effect of ATRA on FLT3-ITD AML cells, we investigated the suitability of a combination of ATRA and DNA damage drug SN38. In vitro experiments showed that this combinatorial approach effectively inhibited the proliferation of FLT3-ITD cells and induced cell apoptosis in AML. In vivo experiments confirmed that the combination could substantially improve the anti-tumor effect of SN38. Taken together, our results indicate that ATRA down-regulates Chk1 in FLT3-ITD AML cells, and the combination of ATRA and SN38 significantly improves the anti-tumor effect of either ATRA or SN38 when used alone.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tretinoína/farmacologia , Adulto , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Pré-Escolar , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitose/efeitos dos fármacos , Cultura Primária de Células , Inibidores de Proteínas Quinases/uso terapêutico , Sequências de Repetição em Tandem/genética , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Tretinoína/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/genética
17.
Invest New Drugs ; 38(5): 1272-1281, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31872348

RESUMO

Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a novel highly selective CDK9 inhibitor, JSH-009, which exhibited high potency against CDK9 and displayed great selectivity over 468 kinases/mutants. It also demonstrates impressive in vitro and in vivo antileukemic efficacy in preclinical models of AML, which makes JSH-009 a useful pharmacological tool for elucidating CDK9-mediated transcription and a novel therapeutic candidate for AML.


Assuntos
Antineoplásicos/uso terapêutico , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
18.
J Econ Entomol ; 113(1): 451-460, 2020 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-31773146

RESUMO

Apolygus lucorum (Meyer-Dür) is a destructive pest to >280 plants. Major economic significance and pesticide resistance issues have created a need for integrated pest management (e.g., RNAi, entomopathogen-based bioinsecticides) for A. lucorum. To better develop these control strategies, large-scale genetic studies involving gene-expression analysis are required and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the most commonly used method. However, there have been no reports on appropriate reference genes in A. lucorum. Here, we evaluated nine widely utilized reference genes including EF1γ, RPL32, RPL27, SDH, TBP, ACT, ACT2, GAPDH, and ßTUB for their expression stabilities in A. lucorum under five different conditions i.e., life stage, tissue, sex, dsRNA injection, and entomopathogen infection. Based on the gene stability ranking calculated by RefFinder, which integrates four algorithms (geNorm, delta Ct method, NormFinder, and BestKeeper), we recommend RPL27 and RPL32 as the most appropriate reference genes for molecular studies in different life stages and tissues; GAPDH and EF1γ for different sexes and entomopathogen infection studies; and RPL27 and EF1γ for RNAi studies. The results of this study will help improve the accuracy and reliability for normalizing the RT-qPCR data for further molecular analysis in A. lucorum.


Assuntos
Heterópteros , Animais , Perfilação da Expressão Gênica , Plantas , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Padrões de Referência , Reprodutibilidade dos Testes
19.
Mol Biomed ; 1(1): 14, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-34765997

RESUMO

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 µM (mice) and 1.6 µM (rats) at 12 h, which is over 200-fold higher than the EC50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy. Supplementary Information: The online version contains supplementary material available at 10.1186/s43556-020-00018-9.

20.
Mol Biomed ; 1(1): 14, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-35006425

RESUMO

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 µM (mice) and 1.6 µM (rats) at 12 h, which is over 200-fold higher than the EC50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy.

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