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1.
Cancer Med ; 13(17): e70210, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39240189

RESUMO

BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts. METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage. RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts. CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.


Assuntos
Neoplasias do Endométrio , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Humanos , Animais , Camundongos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/genética , Linhagem Celular Tumoral , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Sequenciamento do Exoma , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Gradação de Tumores , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/antagonistas & inibidores , Oxazepinas , Sulfonamidas , Pirazinas , Benzamidas , Imidazóis
2.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(9): 967-973, 2024.
Artigo em Chinês | MEDLINE | ID: mdl-39267513

RESUMO

OBJECTIVES: To study the effects and mechanisms of tetramethylpyrazine (TMP) on tumor necrosis factor-α (TNF-α)-induced inflammatory injury in human coronary artery endothelial cells (HCAEC). METHODS: HCAEC were randomly divided into four groups: the control group (no treatment), the model group (treated with TNF-α, 50 ng/mL for 24 hours), the TMP group (pre-treated with TMP, 80 µg/mL for 12 hours followed by TNF-α treatment for 24 hours), and the SIRT1 inhibitor group (pre-treated with TMP and the specific SIRT1 inhibitor EX527 for 12 hours followed by TNF-α treatment for 24 hours). Cell viability was assessed using the CCK-8 method, lactate dehydrogenase (LDH) activity was measured using an LDH assay kit, reactive oxygen species (ROS) levels were observed using DCFH-DA staining, expression of pyroptosis-related proteins was detected by Western blot, and SIRT1 expression was analyzed using immunofluorescence staining. RESULTS: Compared to the control group, the model group showed decreased cell viability, increased LDH activity, ROS level and expression of pyroptosis-related proteins, and decreased SIRT1 expression (P<0.05). Compared to the model group, the TMP group exhibited increased cell viability, decreased LDH activity, ROS level and expression of pyroptosis-related proteins, and increased SIRT1 expression (P<0.05). In comparison to the TMP group, the SIRT1 inhibitor group showed decreased cell viability, increased LDH activity, ROS level and expression of pyroptosis-related proteins, and decreased SIRT1 expression (P<0.05). CONCLUSIONS: TMP may attenuate TNF-α-induced inflammatory injury in HCAEC, which is associated with the inhibition of pyroptosis and activation of the SIRT1 signaling pathway.


Assuntos
Células Endoteliais , Pirazinas , Espécies Reativas de Oxigênio , Transdução de Sinais , Sirtuína 1 , Fator de Necrose Tumoral alfa , Sirtuína 1/metabolismo , Sirtuína 1/fisiologia , Humanos , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Células Cultivadas , Inflamação/tratamento farmacológico
3.
Rinsho Ketsueki ; 65(8): 727-731, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-39231699

RESUMO

A 72-year-old woman with relapsed FLT3-ITD-positive acute myeloid leukemia was treated with gilteritinib and achieved complete remission with incomplete hematological recovery. However, two months later, she developed optic nerve infiltration and lost vision in her right eye while maintaining hematological remission on gilteritinib. Intrathecal injection of cytotoxic drugs reduced the number of blasts in the cerebrospinal fluid (CSF), but her vision did not recover. At the onset of optic nerve infiltration, at a dose of 80 mg/day gilteritinib, the plasma trough and CSF levels of gilteritinib were 151.9 ng/ml and 1.9 ng/ml, respectively, with a central nervous system (CNS) penetration rate of 1.3%. Hematologic progressive disease (PD) was detected after 40 days, and the patient died one month later. Target sequencing at the time of hematologic PD revealed the FLT3 F691L mutation, which is known to confer resistance to gilteritinib. In this patient, pharmacokinetic (low CNS penetration of gilteritinib) and pharmacodynamic (acquisition of a drug resistance mutation) mechanisms were thought to be responsible for the CNS relapse and hematologic PD, respectively. We believe this is a valuable case to report considering the scarcity of data on CNS penetration of FLT3 inhibitors and their effects on CNS disease in the literature.


Assuntos
Compostos de Anilina , Leucemia Mieloide Aguda , Pirazinas , Recidiva , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Idoso , Feminino , Compostos de Anilina/uso terapêutico , Compostos de Anilina/administração & dosagem , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Nervo Óptico/patologia , Mutação , Evolução Fatal
4.
Int J Mol Sci ; 25(17)2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39273395

RESUMO

FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML). FLT3 mutations in AML represent a challenging clinical scenario characterized by a high rate of relapse, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The advent of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin and gilteritinib, has shown promise in achieving complete remission. However, a substantial proportion of patients still experience relapse following TKI treatment, necessitating innovative therapeutic strategies. This review critically addresses the current landscape of TKI treatments for FLT3+ AML, with a particular focus on gilteritinib. Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated efficacy in targeting the mutant FLT3 receptor, thereby inhibiting aberrant signaling pathways that drive leukemic proliferation. However, monotherapy with TKIs may not be sufficient to eradicate AML blasts. Specifically, we provide evidence for integrating gilteritinib with mammalian targets of rapamycin (mTOR) inhibitors and interleukin-15 (IL-15) complexes. The combination of gilteritinib, mTOR inhibitors, and IL-15 complexes presents a compelling strategy to enhance the eradication of AML blasts and enhance NK cell killing, offering a potential for improved patient outcomes.


Assuntos
Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pirazinas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Mutação , Transdução de Sinais/efeitos dos fármacos , Compostos de Anilina/uso terapêutico , Compostos de Anilina/farmacologia
5.
Molecules ; 29(17)2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39274876

RESUMO

Gaussia luciferase (Gluc) is currently known as the smallest naturally secreted luciferase. Due to its small molecular size, high sensitivity, short half-life, and high secretion efficiency, it has become an ideal reporter gene and is widely used in monitoring promoter activity, studying protein-protein interactions, protein localization, high-throughput drug screening, and real-time monitoring of tumor occurrence and development. Although studies have shown that different Gluc mutations exhibit different bioluminescent properties, their mechanisms have not been further investigated. The purpose of this study is to reveal the relationship between the conformational changes of Gluc mutants and their bioluminescent properties through molecular dynamics simulation combined with neural relationship inference (NRI) and Markov models. Our results indicate that, after binding to the luciferin coelenterazine (CTZ), the α-helices of the 109-119 residues of the Gluc Mutant2 (GlucM2, the flash-type mutant) are partially unraveled, while the α-helices of the same part of the Gluc Mutant1 (GlucM1, the glow-type mutant) are clearly formed. The results of Markov flux analysis indicate that the conformational differences between glow-type and flash-type mutants when combined with luciferin substrate CTZ mainly involve the helicity change of α7. The most representative conformation and active pocket distance analysis indicate that compared to the flash-type mutant GlucM2, the glow-type mutant GlucM1 has a higher degree of active site closure and tighter binding. In summary, we provide a theoretical basis for exploring the relationship between the conformational changes of Gluc mutants and their bioluminescent properties, which can serve as a reference for the modification and evolution of luciferases.


Assuntos
Luciferases , Cadeias de Markov , Simulação de Dinâmica Molecular , Luciferases/metabolismo , Luciferases/genética , Luciferases/química , Conformação Proteica , Mutação , Animais , Copépodes/enzimologia , Copépodes/genética , Imidazóis/química , Imidazóis/metabolismo , Ligação Proteica , Medições Luminescentes , Pirazinas
6.
PLoS One ; 19(9): e0299342, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39264896

RESUMO

Monkeypox (MPXV) is one of the infectious viruses which caused morbidity and mortality problems in these years. Despite its danger to public health, there is no approved drug to stand and handle MPXV. On the other hand, drug repurposing is a promising screening method for the low-cost introduction of approved drugs for emerging diseases and viruses which utilizes computational methods. Therefore, drug repurposing is a promising approach to suggesting approved drugs for the MPXV. This paper proposes a computational framework for MPXV antiviral prediction. To do this, we have generated a new virus-antiviral dataset. Moreover, we applied several machine learning and one deep learning method for virus-antiviral prediction. The suggested drugs by the learning methods have been investigated using docking studies. The target protein structure is modeled using homology modeling and, then, refined and validated. To the best of our knowledge, this work is the first work to study deep learning methods for the prediction of MPXV antivirals. The screening results confirm that Tilorone, Valacyclovir, Ribavirin, Favipiravir, and Baloxavir marboxil are effective drugs for MPXV treatment.


Assuntos
Antivirais , Aprendizado Profundo , Reposicionamento de Medicamentos , Monkeypox virus , Antivirais/farmacologia , Monkeypox virus/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Pirazinas/farmacologia , Simulação de Acoplamento Molecular , Dibenzotiepinas , Amidas/farmacologia , Ribavirina/farmacologia , Triazinas/farmacologia , Mpox/tratamento farmacológico , Mpox/virologia , Humanos , Aprendizado de Máquina , Morfolinas , Piridonas
7.
Sci Rep ; 14(1): 20006, 2024 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-39198493

RESUMO

Acute lung injury (ALI) is a severe clinical respiratory condition characterized by high rates of mortality and morbidity, for which effective treatments are currently lacking. In this study, lipopolysaccharide (LPS) was used to induce ALI mice, demonstrating the efficacy of tetramethylpyrazine (TMP) in ameliorating ALI. Subsequent we perfored high-throughput sequencing analysis and used Targetscan 8.0 and miRWalk 3.0 databases to predict the interaction between microRNAs and destrin (DSTN), ultimately identifying miR-369-3p as the focus of the investigation. The adenovirus carrying miR-369-3p was administered one week prior to LPS-induced in order to assess its potential efficacy in ameliorating ALI in mice. The findings indicated that the overexpression of miR-369-3p resulted in enhanced lung function, reduced pulmonary edema, inflammation, and permeability in LPS-induced ALI mice, while the suppression of miR-369-3p exacerbated the damage in these mice. Furthermore, the beneficial effects of TMP on LPS-induced ALI were negated by the downregulation of miR-369-3p. The results of our study demonstrate that TMP mitigates LPS-induced ALI through upregulation of miR-369-3p. Consequently, the findings of this study advocate for the clinical utilization of TMP in ALI treatment, with miR-369-3p emerging as a promising target for future ALI interventions.


Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos , MicroRNAs , Pirazinas , Animais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/genética , Pirazinas/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos , Masculino , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
8.
Int Immunopharmacol ; 140: 112800, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39096875

RESUMO

Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.


Assuntos
Ferroptose , Infarto da Artéria Cerebral Média , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Estresse Oxidativo , Traumatismo por Reperfusão , Tionas , Tiofenos , Animais , Ferroptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Tionas/farmacologia , Tionas/uso terapêutico , Células PC12 , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Ratos , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Modelos Animais de Doenças , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Pirazinas
9.
Future Oncol ; 20(12): 717-726, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-39132937

RESUMO

What is this summary about? This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.How was the research done? The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.What were the results? After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).


Assuntos
Adenina , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Piperidinas , Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Humanos , Piperidinas/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos/uso terapêutico , Pirazinas/uso terapêutico , Tiazóis/uso terapêutico , Resultado do Tratamento
10.
Luminescence ; 39(8): e4837, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39113185

RESUMO

During the pandemic, Favipiravir (FVP) and Molnupiravir (MPV) have been widely used for COVID-19 treatment, leading to their presence in the environment. A green synchronous spectrofluorimetric method was developed to simultaneously detect them in environmental water, human plasma, and binary mixtures. Maximum fluorescence intensity was achieved at pH 8, with MPV exhibiting two peaks at 300 and 430 nm, and FVP showing one peak at 430 nm. A fluorescence subtraction method effectively removed interference, enabling direct determination of MPV at 300 nm and FVP at 430 nm. The method showed linearity within 2-13 ng/mL for FVP and 50-600 ng/mL for MPV, with recoveries of 100.35% and 100.12%, respectively. Limits of detection and quantification were 0.19 and 0.57 ng/mL for FVP and 10.52 and 31.88 ng/mL for MPV. Validation according to ICH and FDA guidelines yielded acceptable results. The method demonstrated good recoveries of FVP and MPV in pharmaceuticals, tap water and Nile water (99.62% ± 0.96% and 99.69% ± 0.64%) as per ICH guidelines and spiked human plasma (94.87% ± 2.111% and 94.79% ± 1.605%) following FDA guidelines, respectively. Its environmental friendliness was assessed using Green Analytical Procedure Index (GAPI) and the Analytical Greenness Metric (AGREE) tools.


Assuntos
Amidas , Antivirais , Pirazinas , Espectrometria de Fluorescência , Pirazinas/análise , Pirazinas/sangue , Pirazinas/química , Amidas/análise , Amidas/química , Amidas/sangue , Espectrometria de Fluorescência/métodos , Humanos , Antivirais/análise , Antivirais/sangue , Uridina/análise , Uridina/sangue , Limite de Detecção , Citidina/análise , Citidina/sangue , Citidina/análogos & derivados , Tratamento Farmacológico da COVID-19 , Mercaptopurina/sangue , Mercaptopurina/análise , SARS-CoV-2 , Hidroxilaminas
12.
J Agric Food Chem ; 72(33): 18630-18637, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39116173

RESUMO

The formation pathway and mechanism of various pyrazines were investigated during the thermal treatment of the alanine-xylose Amadori compound (Ala-ARP) and exogenous alanine (Ala). 15N-labeled Ala was used to coheated with Ala-ARP to clarify the nitrogen sources and the respective contributions of exogenous Ala and the regenerated Ala released from Ala-ARP to different pyrazine formation. It was found that exogenous Ala exhibited a priority in capturing glyoxal (GO) to form pyrazine during the thermal degradation of ARP. Compared to the Ala-methylglyoxal (MGO) model, a lower activation energy was required for the Ala-GO reaction, where the reaction dynamics of Ala-GO followed a zero-order model. In addition to forming pyrazine, the interaction between existing exogenous Ala and GO would accelerate the thermal degradation of Ala-ARP and retro-aldolization reaction of deoxyxylosones (DXs) to α-dicarbonyls. During this process, the release of regenerated Ala and MGO was promoted. Accordingly, as GO was expended by exogenous Ala during the initial stage of ARP-Ala degradation, the condensation between regenerated Ala and MGO became intensified, leading to the generation of methylpyrazine and 2,5-dimethylpyrazine. As a result, in the thermally treated mixture of Ala-ARP and exogenous Ala, 55% of the formed pyrazine originated from exogenous Ala, while 63% of the formed methylpyrazine and 57% of the formed 2,5-dimethylpyrazine were derived from regenerated Ala (120 °C, 30 min).


Assuntos
Alanina , Temperatura Alta , Pirazinas , Pirazinas/química , Alanina/química , Alanina/análogos & derivados , Marcação por Isótopo , Nitrogênio/química , Xilose/química , Reação de Maillard , Cinética
13.
J Med Chem ; 67(16): 14466-14477, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39088797

RESUMO

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.


Assuntos
Antineoplásicos , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Pirazóis , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Humanos , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Pirazinas/farmacologia , Pirazinas/síntese química , Pirazinas/química , Pirazinas/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Camundongos , Mutação , Ratos
14.
J Med Chem ; 67(17): 15569-15585, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39208150

RESUMO

Allosteric modulators of the metabotropic group II receptors, mGluR2 and mGluR3, have been widely explored due to their ability to modulate cognitive and neurological functions in mood disorders, although none have been approved yet. In our search for new and selective mGluR2 negative allosteric modulators (NAMs), series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives were identified from our published series of 1,3,5-trisubstituted pyrazoles. SAR evolution of the initial hit resulted in 100-fold improvement in the mGluR2 NAM potency and subsequent selection of compound 11 based on its overall profile, including selectivity and ADMET properties. Further pharmacokinetic-pharmacodynamic (PK-PD) relationship built showed that compound 11 occupied the mGluR2 receptor in a dose-dependent manner. Additionally, the compound revealed in vivo activity in V-maze as a model of cognition from a dose of 0.32 mg/kg. Compound 11 was selected to be evaluated further.


Assuntos
Cognição , Pirazóis , Receptores de Glutamato Metabotrópico , Animais , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica/efeitos dos fármacos , Cognição/efeitos dos fármacos , Relação Estrutura-Atividade , Ratos , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Pirazóis/farmacocinética , Humanos , Pirazinas/farmacologia , Pirazinas/química , Pirazinas/farmacocinética , Pirazinas/síntese química , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Descoberta de Drogas
15.
Antiviral Res ; 230: 105980, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39117284

RESUMO

In search of novel therapeutic options to treat influenza virus (IV) infections, we previously identified a series of inhibitors that act by disrupting the interactions between the PA and PB1 subunits of the viral RNA polymerase. These compounds showed broad-spectrum antiviral activity against human influenza A and B viruses and a high barrier to the induction of drug resistance in vitro. In this short communication, we investigated the effects of combinations of the PA-PB1 interaction inhibitor 54 with oseltamivir carboxylate (OSC), zanamivir (ZA), favipiravir (FPV), and baloxavir marboxil (BXM) on the inhibition of influenza A and B virus replication in vitro. We observed a synergistic effect of the 54/OSC and 54/ZA combinations and an antagonistic effect when 54 was combined with either FPV or BXM. Moreover, we demonstrated the efficacy of 54 against highly pathogenic avian influenza viruses (HPAIVs) both in cell culture and in the embryonated chicken eggs model. Finally, we observed that 54 enhances OSC protective effect against HPAIV replication in the embryonated eggs model. Our findings represent an advance in the development of alternative therapeutic strategies against both human and avian IV infections.


Assuntos
Antivirais , Sinergismo Farmacológico , Vírus da Influenza A , Oseltamivir , Pirazinas , Proteínas Virais , Replicação Viral , Oseltamivir/farmacologia , Oseltamivir/análogos & derivados , Animais , Antivirais/farmacologia , Humanos , Replicação Viral/efeitos dos fármacos , Pirazinas/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Embrião de Galinha , Proteínas Virais/metabolismo , Proteínas Virais/antagonistas & inibidores , Amidas/farmacologia , Dibenzotiepinas/farmacologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/fisiologia , Zanamivir/farmacologia , Triazinas/farmacologia , Piridonas/farmacologia , Influenza Aviária/tratamento farmacológico , Influenza Aviária/virologia , Morfolinas/farmacologia , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Cães , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , RNA Polimerases Dirigidas por DNA/metabolismo , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Linhagem Celular , Células Madin Darby de Rim Canino
16.
Leuk Res ; 145: 107564, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39180903

RESUMO

The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory (R/R) FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but the overall survival (OS) is only approximately 20 % and few patients achieve deep and/ or durable response. We retrospectively analyzed 29 R/R FLT3mut AML patients treated on triplet regimens (gilteritinib+ venetoclaxï¼»VEN] +azacitidineï¼»AZA]). Nineteen patients (65.5 %) had received prior FLT3 inhibitor therapy. The modified composite complete remission (mCRc) rate was 62.1 % (n = 18; CR, 4/29,13.8 %; CRi, 6/29, 20.7 %; MLFS, 8/29, 27.6 %). Among 18 patients achieved mCRc, FLT3-PCR negativity was 94.4 % (n=17), and flow-cytometry negativity was 77.7 % (n=14). The mCRc rate was 70 % (n=7) in 10 patients without prior FLT3 TKI exposure and 57.8 % (n=11) in 19 patients with prior FLT3 TKI exposure (P=0.52). At the end of the first cycle, the median time to ANC > 0.5× 109/L was 38 days and platelet > 50× 109/L was 31 days among responders, but 60-day mortality was 0 %. The estimated 2-year OS was 60.9 % for all R/R FLT3mut patients. The 1-year OS was 80 % and 58.8 % in patients without and with prior FLT3 TKI exposure, respectively (P=0.79). The estimated 2-year OS was 62 % in 19 (65.5 %) patients who received allo-HSCT after triplet therapy and 37 % in 10 patients who did not receive allo-HSCT (P=0.03). In conclusion, triplet therapy with gilteritinib, VEN, and AZA is effective and safe and an excellent frontline option for R/R FLT3mut AML.


Assuntos
Compostos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Pirazinas , Sulfonamidas , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Masculino , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/genética , Feminino , Pessoa de Meia-Idade , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Estudos Retrospectivos , Compostos de Anilina/uso terapêutico , Adulto , Pirazinas/uso terapêutico , Pirazinas/administração & dosagem , Azacitidina/uso terapêutico , Azacitidina/administração & dosagem , Mutação , Tiofenos/uso terapêutico , Tiofenos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos
17.
Cell Mol Life Sci ; 81(1): 331, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39107572

RESUMO

The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, PIEZO1 activation resulted in intracellular F-actin rearrangement, elevated mitochondrial ROS levels and induction of mitochondrial fragmentation upon PIEZO1 activation, as well as increased expression of anti-inflammatory genes. In vivo, ApoE-/- mice treated with Yoda1 exhibited regression of atherosclerosis, enhanced stability of advanced lesions, reduced plaque size and necrotic core, increased collagen content, and reduced expression levels of inflammatory markers. Our findings propose PIEZO1 as a novel and potential therapeutic target in atherosclerosis.


Assuntos
Apoptose , Aterosclerose , Células Espumosas , Canais Iônicos , Macrófagos , Fagocitose , Animais , Canais Iônicos/metabolismo , Canais Iônicos/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Camundongos , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Tiofenos/farmacologia , Masculino , Espécies Reativas de Oxigênio/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/genética , Mitocôndrias/metabolismo , Pirazinas , Tiadiazóis
18.
J Pharm Biomed Anal ; 251: 116445, 2024 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-39214029

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as icotinib, osimertinib, and aumolertinib have emerged as promising treatment options for EGFR mutated Non-small cell lung cancer (NSCLC) patients. Additionally, anlotinib, an anti-angiogenic agent targeting VEGFR, FGFR, and PDGFR, has been used in combination with EGFR-TKIs in NSCLC cases. A method utilizing ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for quantifying icotinib, osimertinib, aumolertinib and anlotinib simultaneously in clinical TDM. The chromatographic separation was performed using a Kinetex C18 column (100 mm × 2.1 mm) and an elution gradient of ammonium acetate in water acidified with 0.1 % formic acid and in acetonitrile. The assay was validated over a linear range of 4-2000 ng/mL for icotinib, 2-1000 ng/mL for osimertinib, 1-500 ng/mL for aumolertinib, and 0.8-400 ng/mL for anlotinib, following the guidelines on bioanalytical methods by FDA. The quantification method exhibited satisfactory performance in terms of selectivity, accuracy (from 91.3 % to 107 %), precision (intra- and inter-day coeffficients of variation ranged from 0.944 % to 7.48 %), linearity, recovery (from 86.0 % to 91.9 %), matrix effect (IS-normalized matrix factors were from 96.7 % to 102 %), and stability. Overall, the method proved to be sensitive, reliable, and straightforward, enabling successful simultaneous determination of blood concentrations of icotinib, osimertinib, aumolertinib, and anlotinib in patients. The validity of the method has been confirmed across various instruments.


Assuntos
Acrilamidas , Compostos de Anilina , Éteres de Coroa , Monitoramento de Medicamentos , Indóis , Quinazolinas , Quinolinas , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Quinolinas/sangue , Quinolinas/uso terapêutico , Quinolinas/farmacocinética , Indóis/sangue , Indóis/farmacocinética , Indóis/uso terapêutico , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Acrilamidas/sangue , Compostos de Anilina/sangue , Quinazolinas/sangue , Quinazolinas/uso terapêutico , Quinazolinas/farmacocinética , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Reprodutibilidade dos Testes , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Pirazinas/sangue , Pirazinas/farmacocinética , Pirazinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/sangue , Espectrometria de Massa com Cromatografia Líquida , Benzamidas , Pirimidinas
19.
J Cancer Res Clin Oncol ; 150(8): 395, 2024 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-39180576

RESUMO

Traditionally, the D1228 E/G/H/N mutation has been thought to cause Type I MET-TKI resistance. We reported a 75-year-old female with non-small cell lung cancer harboring MET exon 14 skipping mutation, who developed acquired MET D1228H mutation induced by capmatinib treatment. Interestingly, the patient demonstrated marked response to second-line savolitinib treatment with the duration of response of 19 months and several additional metastatic lesions appeared. Pathological assessment of rebiopsy sample showed adenocarcinoma and targeted next-generation sequencing revealed the loss of MET D1228H mutation and presence of MET p.Y1230N mutation. In response, the treatment regimen was amended to include a daily administration of 60 mg of cabozantinib, which resulted in moderate size reduction of the tumours. The switch of resistance mutations indicated that different type Ib MET inhibitors may exhibit distinct mechanisms of resistance. We call for futher studies on resistance based on patient-derived pre-clinical models including patient-derived tumor-like cell clusters, patient-derived organoids, and patient-derived xenografts.


Assuntos
Adenocarcinoma de Pulmão , Resistencia a Medicamentos Antineoplásicos , Éxons , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/genética , Feminino , Idoso , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Benzamidas , Acrilamidas/uso terapêutico , Triazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Imidazóis , Pirazinas
20.
Food Chem ; 460(Pt 2): 140614, 2024 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-39089013

RESUMO

Migraine as a common neurological disorder still lacks effective therapies. Tetramethylpyrazine (TMP) is the main bioactive component from Ligusticum chuanxiong hort., a traditional edible-medicinal herb. This study aimed to investigate the action of TMP on migraine by metabolomics with mass spectrometry imaging (MSI) analysis and molecular exploring, including random forest model analysis, KEGG enrichment analysis and metabolite-metabolite interaction network analysis. The results indicated that 26 key representative metabolic biomarkers were identified, especially γ-glu-cys, which were highly related to glutathione (GSH) metabolism. MSI found the abundance of eleven endogenous metabolites were modulated by TMP, particularly glucose, the most important energy metabolism molecule, and GSH were increased that maintains intracellular redox balance, which was consistent with activation of Nrf2 signals by TMP. These findings provide insights into the effectiveness of metabolomics integrated with MSI in explaining the metabolic mechanisms of TMP, and afford valuable information for healthy development of TMP in migraine.


Assuntos
Espectrometria de Massas , Metabolômica , Transtornos de Enxaqueca , Pirazinas , Pirazinas/metabolismo , Pirazinas/análise , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/tratamento farmacológico , Humanos , Animais , Ratos , Ligusticum/química , Ligusticum/metabolismo , Biomarcadores/metabolismo , Biomarcadores/análise , Ratos Sprague-Dawley , Masculino , Glutationa/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/química
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