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1.
Oncoimmunology ; 10(1): 1943234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589290

RESUMO

TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167, and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 or XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-κB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1, and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest the use of the orally available inhibitor OTSSP167 in combination treatment with venetoclax for TRAF1 overexpressing CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B , Naftiridinas/uso terapêutico , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Fator 1 Associado a Receptor de TNF/genética
2.
Nat Commun ; 12(1): 4996, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404793

RESUMO

Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.


Assuntos
Antivirais/química , Antivirais/farmacologia , Microscopia Crioeletrônica , Infecções por HTLV-I/tratamento farmacológico , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Amidas , Domínio Catalítico , Deltaretrovirus , Farmacorresistência Viral/efeitos dos fármacos , Integrase de HIV/efeitos dos fármacos , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Naftiridinas/farmacologia , Piperazinas , Piridonas , Proteínas Recombinantes
3.
Nat Commun ; 12(1): 4920, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389715

RESUMO

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.


Assuntos
Mesotelioma Maligno/genética , Oncogenes/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Animais , Asbestos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mesotelioma Maligno/induzido quimicamente , Mesotelioma Maligno/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Naftiridinas/farmacologia , Polirribossomos/efeitos dos fármacos , Polirribossomos/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , RNA Mensageiro/metabolismo , Células Tumorais Cultivadas
4.
Nat Protoc ; 16(8): 3954-3980, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34215863

RESUMO

Naive human pluripotent stem cells (hPSCs) can be used to generate mature human cells of all three germ layers in mouse-human chimeric embryos. Here, we describe a protocol for generating mouse-human chimeric embryos by injecting naive hPSCs converted from the primed state. Primed hPSCs are treated with a mammalian target of rapamycin inhibitor (Torin1) for 3 h and dissociated to single cells, which are plated on mouse embryonic fibroblasts in 2iLI medium, a condition essentially the same for culturing mouse embryonic stem cells. After 3-4 d, bright, dome-shaped colonies with mouse embryonic stem cell morphology are passaged in 2iLI medium. Established naive hPSCs are injected into mouse blastocysts, which produce E17.5 mouse embryos containing 0.1-4.0% human cells as quantified by next-generation sequencing of 18S ribosomal DNA amplicons. The protocol is suitable for studying the development of hPSCs in mouse embryos and may facilitate the generation of human cells, tissues and organs in animals.


Assuntos
Quimera/embriologia , Embrião de Mamíferos/fisiologia , Células-Tronco Embrionárias/fisiologia , Fibroblastos/fisiologia , Células-Tronco Pluripotentes/fisiologia , Amidas/farmacologia , Animais , Embrião de Mamíferos/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Feminino , Humanos , Camundongos , Naftiridinas/farmacologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Piridinas/farmacologia
5.
Cell Death Dis ; 12(7): 710, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267188

RESUMO

Alcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.


Assuntos
Fígado Gorduroso Alcoólico/metabolismo , Proteínas Ativadoras de GTPase/deficiência , Fígado/metabolismo , PPAR alfa/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Fígado Gorduroso Alcoólico/prevenção & controle , Feminino , Proteínas Ativadoras de GTPase/genética , Mediadores da Inflamação , Fígado/efeitos dos fármacos , Fígado/ultraestrutura , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Naftiridinas/farmacologia , Oxirredução , Estresse Oxidativo , PPAR alfa/genética , Transdução de Sinais
6.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071360

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.


Assuntos
Benzotiazóis/farmacologia , Dano ao DNA , Replicação do DNA/efeitos dos fármacos , Naftiridinas/farmacologia , Quinuclidinas/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Replicação do DNA/genética , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , RNA Polimerase I/antagonistas & inibidores , RNA Polimerase I/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
7.
PLoS Negl Trop Dis ; 15(6): e0009511, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34166393

RESUMO

BACKGROUND: Schistosomiasis is highly prevalent in Africa. Praziquantel is effective against adult schistosomes but leaves prepatent stages unaffected-which is a limit to patient management and elimination. Given the large-scale use of praziquantel, development of drug resistance by Schistosoma is feared. Antimalarials are promising drugs for alternative treatment strategies of Schistosoma infections. Development of drugs with activity against both malaria and schistosomiasis is particularly appealing as schistosome infections often occur concomitantly with malaria parasites in sub-Saharan Africa. Therefore, antiplasmodial compounds were progressively tested against Schistosoma in vitro, in mice, and in a clinical study. RESULTS: Amongst 16 drugs and 1 control tested, pyronaridine, methylene blue and 5 other antimalarials were highly active in vitro against larval stage schistosomula with a 50% inhibitory concentration below 10 µM. Both drugs were lethal to ex vivo adult worms tested at 30 µM with methylene blue also active at 10 µM. Pyronaridine treatment of mice infected with S. mansoni at the prepatent stage reduced worm burden by 82% and cured 7 out of 12 animals, however in mice adult stages remained viable. In contrast, methylene blue inhibited adult worms by 60% but cure was not achieved. In an observational pilot trial in Gabon in children, the antimalarial drug combination pyronaridine-artesunate (Pyramax) reduced S. haematobium egg excretion from 10/10 ml urine to 0/10 ml urine, and 3 out of 4 children were cured. CONCLUSION: Pyronaridine and methylene blue warrant further investigation as candidates for schistosomiasis treatment. Both compounds are approved for human use and evidence for their potential as antischistosomal compounds can be obtained directly from clinical testing. Particularly, pyronaridine-artesunate, already available as an antimalarial drug, calls for further clinical evaluation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03201770.


Assuntos
Antiprotozoários/farmacologia , Naftiridinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose Urinária/tratamento farmacológico , Animais , Antimaláricos/farmacologia , Artesunato/farmacologia , Criança , Combinação de Medicamentos , Gabão , Humanos , Larva/efeitos dos fármacos , Azul de Metileno/farmacologia , Camundongos , Schistosoma haematobium/efeitos dos fármacos , Schistosoma mansoni/crescimento & desenvolvimento , Esquistossomose mansoni/tratamento farmacológico
8.
Nucleic Acids Res ; 49(9): 5159-5176, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33893802

RESUMO

The eIF4E are a family of initiation factors that bind the mRNA 5' cap, regulating the proteome and the cellular phenotype. eIF4E1 mediates global translation and its activity is controlled via the PI3K/AKT/mTOR pathway. mTOR down-regulation results in eIF4E1 sequestration into an inactive complex with the 4E binding proteins (4EBPs). The second member, eIF4E2, regulates the translatome during hypoxia. However, the exact function of the third member, eIF4E3, has remained elusive. We have dissected its function using a range of techniques. Starting from the observation that it does not interact with 4EBP1, we demonstrate that eIF4E3 recruitment into an eIF4F complex occurs when Torin1 inhibits the mTOR pathway. Ribo-seq studies demonstrate that this complex (eIF4FS) is translationally active during stress and that it selects specific mRNA populations based on 5' TL (UTR) length. The interactome reveals that it associates with cellular proteins beyond the cognate initiation factors, suggesting that it may have 'moon-lighting' functions. Finally, we provide evidence that cellular metabolism is altered in an eIF4E3 KO background but only upon Torin1 treatment. We propose that eIF4E3 acts as a second branch of the integrated stress response, re-programming the translatome to promote 'stress resistance' and adaptation.


Assuntos
Fator de Iniciação 4E em Eucariotos/metabolismo , Fator de Iniciação 4F em Eucariotos/metabolismo , Biossíntese de Proteínas , Estresse Fisiológico/genética , Animais , Células Cultivadas , Fatores de Iniciação em Eucariotos/metabolismo , Humanos , Camundongos , Naftiridinas/farmacologia , Capuzes de RNA/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores
9.
PLoS One ; 16(4): e0248380, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33891611

RESUMO

Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Mutação/efeitos dos fármacos , Naftiridinas/farmacologia , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/genética , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Biomed Res Int ; 2021: 6631848, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33869629

RESUMO

Oral submucous fibrosis (OSMF) is considered a premalignant condition characterized by aggressive fibrosis of the submucosal tissues of the oral cavity reflecting its malignant transformation potential. Activation of transforming growth factor beta (TGF-ß) signaling has been reported to lead increased collagen production and fibrosis. Recently, significant upregulation of TGF-ß1 has been reported in OSMF as compared to normal tissues. Therefore, inhibition of the TGF-ß1 may pave for the development of therapeutics of OSMF. Based on the structure-assisted drug designing, we found "silmitasertib" as potent inhibitor of TGF-ß1. We suggest that this molecule can be validated and implemented for the treatment of OSMF.


Assuntos
Reposicionamento de Medicamentos , Naftiridinas/uso terapêutico , Fibrose Oral Submucosa/tratamento farmacológico , Fenazinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Naftiridinas/química , Naftiridinas/farmacologia , Fibrose Oral Submucosa/patologia , Fenazinas/química , Fenazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Tempo , Fator de Crescimento Transformador beta1/química , Fator de Crescimento Transformador beta1/metabolismo
11.
J Med Chem ; 64(8): 5082-5098, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33834781

RESUMO

Multifunctional entities have recently been attractive for the development of anticancer chemotherapeutic drugs. However, such entities with concurrent CK2 along with cancer stem cell (CSC) inhibitory activities are rare in a single small molecule. Herein, a series of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine derivatives were synthesized using a known CK2 inhibitor, silmitasertib (CX-4945), as the lead compound. Among the resulting compounds, 1c exhibited stronger CK2 inhibitory activity with higher Clk2/CK2 selectivity than CX-4945. Significantly, 1c could modulate the Akt1(ser129)-GSK-3ß(ser9)-Wnt/ß-catenin signaling pathway and inhibit the expression of the stemness marker ALDH1A1, CSC surface antigens, and stem genes, showing potent CSC inhibitory activity. Moreover, 1c also displayed superior pharmacokinetics and antitumor activity compared with CX-4945 sodium salt, without obvious toxicity. The favorable antiproliferative and antitumor activity of 1c, its high inhibitory selectivity for CK2, and its potent inhibition of cancer cell stemness make this molecule a candidate for the treatment of cancer.


Assuntos
Antineoplásicos/química , Caseína Quinase II/antagonistas & inibidores , Naftiridinas/química , Inibidores de Proteínas Quinases/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sítios de Ligação , Caseína Quinase II/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Naftiridinas/metabolismo , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Via de Sinalização Wnt/efeitos dos fármacos
12.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802409

RESUMO

Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Movimento Celular/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Naftiridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Mediadores da Inflamação/farmacologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
13.
Molecules ; 26(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807474

RESUMO

Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. The methods utilised for CK2 can be applied to an array of protein kinases to aid in the discovery of chemical probes to further understand each kinase's biology, with wide-reaching implications for drug development.


Assuntos
Caseína Quinase II/metabolismo , Sondas Moleculares/química , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , COVID-19 , Caseína Quinase II/química , Diclororribofuranosilbenzimidazol/química , Diclororribofuranosilbenzimidazol/farmacologia , Humanos , Sondas Moleculares/metabolismo , Naftiridinas/química , Naftiridinas/farmacologia , Fenazinas/química , Fenazinas/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia
14.
Expert Opin Pharmacother ; 22(10): 1253-1256, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33764251

RESUMO

Introduction: Chronic kidney disease occurs in 40% of subjects with diabetes and increases the risk of cardiovascular death three-fold, compared to having diabetes alone. The non-steroidal mineralocorticoid receptor antagonist finerenone protects against chronic kidney disease in animal models.Areas covered: This evaluation is of a phase 3 trial of finerenone; Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD). In FIDELIO-DKD, finerenone reduced the primary composite outcome of kidney failure, a sustained decrease of at least 40% in eGFR over four weeks, or death from renal causes, from 21.1% to 17.8%, with a good safety profile.Expert opinion: Finerenone is an effective mineralocorticoid receptor antagonist for the treatment of diabetic chronic kidney disease. Recently, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporters 2 (SGLT-2) inhibitors have been added to the list of medicines for use in subjects with this condition. Although finerenone has a different mechanism of action to these medicines, it will need to be tested and shown to be effective in presence of these medicines in diabetic kidney disease, prior to widespread use.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Insuficiência Renal Crônica , Animais , Nefropatias Diabéticas/tratamento farmacológico , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico
16.
Chem Commun (Camb) ; 57(26): 3235-3238, 2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33646236

RESUMO

We demonstrated that a synthetic ligand NA, which selectively binds to a 5'-CAG-3'/5'-CAG-3' triad, induced repeat contractions during DNA polymerase-mediated primer extension through the CAG repeat template. A thorough capillary electrophoresis and sequencing analysis revealed that the d(CAG)20 template gave shortened nascent strands mainly containing 3-6 CTG units in the presence of NA.


Assuntos
DNA/genética , Naftiridinas/farmacologia , Quinolonas/farmacologia , Repetições de Trinucleotídeos/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Eletroforese Capilar , Humanos , Ligantes , Conformação de Ácido Nucleico/efeitos dos fármacos
17.
Nat Commun ; 12(1): 1876, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767183

RESUMO

Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.


Assuntos
COVID-19/patologia , Ciclo do Ácido Cítrico/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Benzamidas/farmacologia , Linhagem Celular , Chlorocebus aethiops , Glucose/metabolismo , Glutamina/metabolismo , Células HEK293 , Humanos , Pulmão/metabolismo , Pulmão/virologia , Morfolinas/farmacologia , Naftiridinas/farmacologia , Pirimidinas/farmacologia , Piruvato Carboxilase/biossíntese , SARS-CoV-2/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
18.
Eur J Med Chem ; 216: 113270, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33765486

RESUMO

ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been pursued as a prime target for the treatment of Alzheimer's disease (AD). In this report, we describe the discovery of BACE1 inhibitors with a 1-amino-3,4-dihydro-2,6-naphthyridine scaffold. Leveraging known inhibitors 2a and 2b, we designed the naphthyridine-based compounds by removing a structurally labile moiety and incorporating pyridine rings, which showed increased biochemical and cellular potency, along with reduced basicity on the amidine moiety. Introduction of a fluorine atom on the pyridine culminated in compound 11 which had improved cellular activity as well as further reduced basicity and demonstrated a robust and sustained cerebrospinal fluid (CSF) Aß reduction in dog. The crystal structure of compound 11 bound to BACE1 confirmed van der Waals interactions between the fluorine on the pyridine and Tyr71 in the flap.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Naftiridinas/química , Inibidores de Proteases/química , Piridinas/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Microssomos/metabolismo , Simulação de Dinâmica Molecular , Naftiridinas/metabolismo , Naftiridinas/farmacologia , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Ratos , Eletricidade Estática , Relação Estrutura-Atividade
19.
Top Curr Chem (Cham) ; 379(2): 13, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33624162

RESUMO

The burgeoning interest in synthesis and biological applications of 1,6-naphthyridines reflects the importance of 1,6-naphthyridines in the synthetic as well as medicinal chemistry fields. Specially, 1,6-naphthyridines are pharmacologically active, with variety of applications such as anticancer, anti-human immunodeficiency virus (HIV), anti-microbial, analgesic, anti-inflammatory and anti-oxidant activities. Although collective recent synthetic developments have paved a path to a wide range of functionalized 1,6-naphthyridines, a complete correlation of synthesis with biological activity remains elusive. The current review focuses on recent synthetic developments from the last decade and a thorough study of the anticancer activity of 1,6-naphthyridines on different cancer cell lines. Anticancer activity has been correlated to 1,6-naphthyridines using the literature on the structure-activity relationship (SAR) along with molecular modeling studies. Exceptionally, at the end of this review, the utility of 1,6-naphthyridines displaying activities other than anticancer has also been included as a glimmering extension.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftiridinas/síntese química , Naftiridinas/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Naftiridinas/química , Relação Estrutura-Atividade
20.
Leukemia ; 35(5): 1267-1278, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33531656

RESUMO

Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Serina-Treonina Quinases TOR/genética , Caseína Quinase II/genética , Linhagem Celular , Linhagem Celular Tumoral , Criança , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Genes Supressores de Tumor/efeitos dos fármacos , Células HEK293 , Humanos , Naftiridinas/farmacologia , Fenazinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transdução de Sinais/efeitos dos fármacos
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