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1.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207177

RESUMO

Huntington's disease (HD) is a multi-system disorder that is caused by expanded CAG repeats within the exon-1 of the huntingtin (HTT) gene that translate to the polyglutamine stretch in the HTT protein. HTT interacts with the proteins involved in gene transcription, endocytosis, and metabolism. HTT may also directly or indirectly affect purine metabolism and signaling. We aimed to review existing data and discuss the modulation of the purinergic system as a new therapeutic target in HD. Impaired intracellular nucleotide metabolism in the HD affected system (CNS, skeletal muscle and heart) may lead to extracellular accumulation of purine metabolites, its unusual catabolism, and modulation of purinergic signaling. The mechanisms of observed changes might be different in affected systems. Based on collected findings, compounds leading to purine and ATP pool reconstruction as well as purinergic receptor activity modulators, i.e., P2X7 receptor antagonists, may be applied for HD treatment.


Assuntos
Doença de Huntington/metabolismo , Nucleotídeos de Purina/metabolismo , Transdução de Sinais , AMP Desaminase/antagonistas & inibidores , AMP Desaminase/metabolismo , Animais , Inibidores Enzimáticos/uso terapêutico , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Fármacos Neuroprotetores/uso terapêutico
2.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207315

RESUMO

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin-RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136-400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Ciclopentanos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neuroblastoma/tratamento farmacológico , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclopentanos/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Proteína NEDD8/antagonistas & inibidores , Proteína NEDD8/metabolismo , Pirimidinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo
4.
Med Clin North Am ; 105(4): 627-641, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34059242

RESUMO

Psoriasis is a systemic inflammatory condition that negatively affects the quality of life and medical health of 125 million individuals globally. Although psoriasis has historically been viewed as a skin-limited disease and managed with topical agents (eg, coal tar, corticosteroids, and vitamin D analogues), the recontextualization of psoriasis as a systemic condition involving multiple organ systems has prompted the development of numerous immunomodulating, systemic agents with more targeted mechanisms of action. This article briefly discusses the indications and nuances of new and developing therapeutic agents for psoriasis management.


Assuntos
Interleucinas/antagonistas & inibidores , Psoríase/patologia , Psoríase/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Ensaios Clínicos como Assunto , Alcatrão/administração & dosagem , Alcatrão/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Psoríase/diagnóstico , Psoríase/psicologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Qualidade de Vida/psicologia , Receptores de Hidrocarboneto Arílico , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico
5.
Molecules ; 26(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066081

RESUMO

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure-activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of 'drug-likeness". Novel promising structures of putative multifunctional ARIs/AOs are designed.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/uso terapêutico , Complicações do Diabetes/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Indóis/uso terapêutico , Aldeído Redutase/metabolismo , Animais , Antioxidantes/química , Complicações do Diabetes/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Indóis/química , Estrutura Molecular , Polímeros/metabolismo , Relação Estrutura-Atividade
6.
Nat Commun ; 12(1): 2607, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972549

RESUMO

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.


Assuntos
Antineoplásicos/uso terapêutico , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Células-Tronco/metabolismo , Idoso , Aminopiridinas/uso terapêutico , Proteínas Estimuladoras de Ligação a CCAAT/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Epigenômica , Evolução Molecular , Feminino , Glicina/análogos & derivados , Glicina/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Família Multigênica , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Piridinas/uso terapêutico , RNA-Seq , Proteínas Repressoras/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Célula Única , Triazinas/uso terapêutico , Proteínas ras/genética
7.
J Med Chem ; 64(9): 5429-5446, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33945278

RESUMO

The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.


Assuntos
Adamantano/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Epóxido Hidrolases/antagonistas & inibidores , Doença Aguda , Adamantano/metabolismo , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Sítios de Ligação , Domínio Catalítico , Permeabilidade da Membrana Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/metabolismo , Meia-Vida , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Pancreatite/tratamento farmacológico , Ratos , Relação Estrutura-Atividade
8.
J Med Chem ; 64(10): 6549-6565, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34000808

RESUMO

Pyroglutamate (pE) modification, catalyzed mainly by glutaminyl cyclase (QC), is prevalent throughout nature and is particularly important in mammals including humans for the maturation of hormones, peptides, and proteins. In humans, the upregulation of QC is involved in multiple diseases and conditions including Alzheimer's disease, Huntington's disease, melanomas, thyroid carcinomas, accelerated atherosclerosis, septic arthritics, etc. This upregulation catalyzes the generation of modified mediators such as pE-amyloid beta (Aß) and pE-chemokine ligand 2 (CCL2) peptides. Not surprisingly, QC has emerged as a reasonable target for the development of therapeutics to combat these diseases and conditions. In this manuscript the deleterious effects of upregulated QC resulting in disease manifestation are reviewed, along with progress on the development of QC inhibitors.


Assuntos
Aminoaciltransferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Aminoaciltransferases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Ácido Pirrolidonocarboxílico/metabolismo , Regulação para Cima
9.
Mol Cell ; 81(11): 2278-2289, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33984284

RESUMO

Agents that induce DNA damage can cure some cancers. However, the side effects of chemotherapy are severe because of the indiscriminate action of DNA-damaging agents on both healthy and cancerous cells. DNA repair pathway inhibition provides a less toxic and targeted alternative to chemotherapy. A compelling DNA repair target is the Fanconi anemia (FA) E3 ligase core complex due to its critical-and likely singular-role in the efficient removal of specific DNA lesions. FA pathway inactivation has been demonstrated to specifically kill some types of cancer cells without the addition of exogenous DNA damage, including cells that lack BRCA1, BRCA2, ATM, or functionally related genes. In this perspective, we discuss the genetic and biochemical evidence in support of the FA core complex as a compelling drug target for cancer therapy. In particular, we discuss the genetic, biochemical, and structural data that could rapidly advance our capacity to identify and implement the use of FA core complex inhibitors in the clinic.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Reparo do DNA/efeitos dos fármacos , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Anemia de Fanconi/tratamento farmacológico , Ubiquitina-Proteína Ligases/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Dano ao DNA , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Proteínas de Grupos de Complementação da Anemia de Fanconi/antagonistas & inibidores , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular/métodos , Morfolinas/uso terapêutico , Pironas/uso terapêutico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Mutações Sintéticas Letais , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas/antagonistas & inibidores , Ubiquitinas/genética , Ubiquitinas/metabolismo
10.
Cancer Res ; 81(4): 1087-1100, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33822745

RESUMO

Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. SIGNIFICANCE: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.


Assuntos
Histona Desmetilases com o Domínio Jumonji/fisiologia , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Processamento Alternativo , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Terapia de Alvo Molecular , Oxigenases/genética , Oxigenases/fisiologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Estudos Retrospectivos
11.
J Med Chem ; 64(9): 5404-5428, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33844533

RESUMO

The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC50 = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC50 = 17.3 nM), strong proapoptotic properties (EC50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC30(Jurkat) > 100 µM).


Assuntos
Compostos de Bifenilo/química , Inibidores Enzimáticos/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Meia-Vida , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
Nutrients ; 13(4)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916690

RESUMO

Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.


Assuntos
Carcinogênese/metabolismo , Neoplasias do Colo/terapia , Microbioma Gastrointestinal/efeitos dos fármacos , Triptofano/metabolismo , Evasão Tumoral/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Colo/microbiologia , Colo/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/microbiologia , Terapia Combinada/métodos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indóis/administração & dosagem , Indóis/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Cinurenina/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/imunologia , Probióticos/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/metabolismo , Simbiose/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
14.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923786

RESUMO

Succinate dehydrogenase (SDH) inhibition with malonate during reperfusion reduced myocardial infarction in animals, whereas its endogenous substrate, succinate, is detected in plasma from STEMI patients. We investigated whether protection by SDH inhibition is additive to that of remote ischemic perconditioning (RIC) in pigs submitted to transient coronary artery occlusion, and whether protective maneuvers influence plasma levels of citric acid cycle metabolites. Forty pigs were submitted to 40 min coronary occlusion and reperfusion, and allocated to four groups (controls, sodium malonate 10 mmol/L, RIC, and malonate + RIC). Plasma was obtained from femoral and great cardiac veins and analyzed by LC-MS/MS. Malonate, RIC, and malonate + RIC reduced infarct size (24.67 ± 5.98, 25.29 ± 3.92 and 29.83 ± 4.62% vs. 46.47 ± 4.49% in controls, p < 0.05), but no additive effects were detected. Enhanced concentrations of succinate, fumarate, malate and citrate were observed in controls during initial reperfusion in the great cardiac vein, and most were reduced by cardioprotective maneuvers. Concentrations of succinate, fumarate, and malate significantly correlated with infarct size. In conclusion, despite the combination of SDH inhibition during reperfusion and RIC did not result in additive protection, plasma concentrations of selected citric acid cycle metabolites are attenuated by protective maneuvers, correlate with irreversible injury, and might become a prognosis tool in STEMI patients.


Assuntos
Ciclo do Ácido Cítrico , Oclusão Coronária/metabolismo , Inibidores Enzimáticos/uso terapêutico , Precondicionamento Isquêmico/métodos , Infarto do Miocárdio/metabolismo , Succinato Desidrogenase/antagonistas & inibidores , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Oclusão Coronária/patologia , Oclusão Coronária/terapia , Ácidos Dicarboxílicos/sangue , Ácidos Dicarboxílicos/metabolismo , Inibidores Enzimáticos/farmacologia , Coração/efeitos dos fármacos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miocárdio/metabolismo , Suínos
15.
Eur J Pharmacol ; 901: 174078, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33839087

RESUMO

The abnormal dietary life style leads to hyperlipidemia and insulin resistance with ectopic lipid accumulation and elevated levels of hepatic glucose development which are the underlying pathological characteristics of fatty liver diseases. The pharmacological inhibition of fatty acid synthase of de novo lipogenesis may regulate the dysfunctional lipid biotransformation and reverse the pathological state of diabetic liver injury. The three pharmacological interventions (PTS; Pterostilbene, ARB; Arbutin, PUR; Purpurin) were administered to manage the condition of diabetic liver injury against the high fat diet (HFD) + Streptozotocin (STZ) 30 mg/kg b.wt. rodent animal model to observe the effect of abnormal fatty acid synthesis. The qRT-PCR was used to evaluate the fatty acid synthase (FASN) expression which is independently allied with diabetes associated fatty liver disorders. To determine the therapeutic potential of three selected drugs, the biochemical parameters and histopathological considerations were utilized. Three subsequent dosage of PTS, ARB and PUR administered (i.e., 30,60 & 120 mg/kg/p.o.) for five weeks significantly alter the serum parameters, oxidative burden in HFD-STZ which, in turn, resulted in diabetic liver injury. It was also revealed that increased mRNA expression of fatty acid synthase (FASN), which is known to promote abnormal fatty acid synthesis through different molecular signaling pathways, was associated with the development of diabetes associated liver injury, this expression was observed to be significantly suppressed by PTS, ARB and PUR treatment. Moreover, the studies of histopathology showed that there was substantial structural improvement after PTS, ARB and PUR treatment. All three selected drugs have been shown to be effective for Diabetic liver injury (DLI) care but PTS shows impressive results compared to other selected drugs.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Hepatopatias/prevenção & controle , Animais , Antraquinonas/uso terapêutico , Antioxidantes/metabolismo , Arbutina/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Dieta Hiperlipídica , Ácido Graxo Sintase Tipo I/biossíntese , Ácido Graxo Sintase Tipo I/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Hepatopatias/etiologia , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico
16.
J Med Chem ; 64(8): 4913-4946, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33822623

RESUMO

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).


Assuntos
Inibidores Enzimáticos/química , Isocitrato Desidrogenase/antagonistas & inibidores , Piridonas/química , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Feminino , Glicina/análogos & derivados , Glicina/uso terapêutico , Meia-Vida , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Mutagênese Sítio-Dirigida , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Piridinas/uso terapêutico , Piridonas/metabolismo , Piridonas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Med Chem ; 64(8): 4677-4696, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33844524

RESUMO

Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aß levels in mice, rats, and dogs in acute and chronic treatment regimens.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Inibidores Enzimáticos/síntese química , Ácidos Picolínicos/síntese química , Tiazinas/síntese química , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Camundongos , Simulação de Dinâmica Molecular , Oxazinas/química , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/uso terapêutico , Ratos , Relação Estrutura-Atividade , Tiazinas/farmacocinética , Tiazinas/uso terapêutico
18.
J Med Chem ; 64(8): 4588-4611, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33792311

RESUMO

The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Glutaminase/antagonistas & inibidores , Compostos Macrocíclicos/química , Sítio Alostérico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glutaminase/metabolismo , Glicólise/efeitos dos fármacos , Meia-Vida , Humanos , Compostos Macrocíclicos/metabolismo , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/uso terapêutico , Camundongos , Camundongos Nus , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
19.
J Med Chem ; 64(8): 4450-4461, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33819035

RESUMO

Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil (1, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin (2) and phloretin (3)). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.


Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Estabilidade de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Fluoruracila/uso terapêutico , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Floretina/química , Floretina/metabolismo , Floretina/uso terapêutico , Florizina/química , Florizina/metabolismo , Florizina/uso terapêutico , Relação Estrutura-Atividade , Distribuição Tecidual
20.
J Med Chem ; 64(8): 4257-4288, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33822624

RESUMO

Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery. From the production and secretion of WNT ligands, their binding to membrane receptors, and the ß-catenin destruction complex to the expansive ß-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling. Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, ß-catenin/coactivators, protein-protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (e.g., LGK-974, PRI-724, and ETC-159) in human clinical trials. Herein we summarize recent progress in the drug discovery and development of small-molecule inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochemical properties, and therapeutic potential. The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted.


Assuntos
Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Sítios de Ligação , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Peptídeos/química , Peptídeos/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Fatores de Transcrição TCF/química , Fatores de Transcrição TCF/metabolismo , Tanquirases/antagonistas & inibidores , Tanquirases/metabolismo , Proteínas Wnt/química , beta Catenina/química , beta Catenina/metabolismo
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