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1.
Medicine (Baltimore) ; 100(39): e27385, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596160

RESUMO

RATIONALE: Although anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib. PATIENTS CONCERNS: A 55-year-old woman with no history of smoking presented to our hospital with a swelling on the left neck. Clinical imaging and histopathological examination revealed a tumor of adenocarcinoma histology in the left upper lung with no CNS metastasis. DIAGNOSES: The patient was diagnosed with ALK-positive lung adenocarcinoma (cT3N3M1b: stage IVA). INTERVENTIONS: She received the second-generation ALK inhibitors, alectinib and brigatinib, in the first and second-line settings, respectively. However, she developed meningeal carcinomatosis. Hence, treatment with lorlatinib was initiated in the third-line setting. OUTCOMES: The symptoms associated with meningeal carcinomatosis, such as disturbance of consciousness and diplopia, improved dramatically. At 8 months from the initiation of lorlatinib, the patient remained well without disease progression. LESSONS: Lorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis.


Assuntos
Aminopiridinas/uso terapêutico , Quinase do Linfoma Anaplásico/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas/uso terapêutico , Carcinomatose Meníngea/tratamento farmacológico , Carcinomatose Meníngea/secundário , Proteínas Tirosina Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/uso terapêutico , Pirazóis/uso terapêutico , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Carcinomatose Meníngea/diagnóstico por imagem , Pessoa de Meia-Idade , Compostos Organofosforados/uso terapêutico , Piperidinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/uso terapêutico
2.
Pharmacol Res Perspect ; 9(5): e00846, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34624174

RESUMO

The COVID-19 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate bioequivalence, using an adaptive study design, of tadalafil in fixed-dose combination (FDC) tablets of macitentan/tadalafil with single macitentan and tadalafil (Canadian-sourced) tablets and assess the effect of food on FDC tablets in healthy subjects. This Phase 1, single-center, open-label, single-dose, two-part, two-period, randomized, crossover study enrolled 62 subjects. Tadalafil bioequivalence as part of FDC of macitentan/tadalafil (10/40 mg) with single-component tablets of macitentan (10 mg) and tadalafil (40 mg) was determined by pharmacokinetic (PK) assessment under fasted conditions. The effect of food on FDC was evaluated under fed and fasted conditions. Fasted 90% confidence intervals (CIs) for geometric mean ratios (GMRs) were within bioequivalence limits for tadalafil and macitentan. Fed and fasted 90% CIs for area under the curve (AUC) GMR were within bioequivalence limits. However, 90% CIs for maximum plasma concentration (Cmax ) GMR for macitentan and tadalafil were outside bioequivalence limits. One FDC-treated subject experienced a serious adverse event of transient ischemic attack (bioequivalence part). To address pandemic-imposed limitations, an adaptive study design was implemented to demonstrate that the FDC tablet was bioequivalent to the free combination of macitentan and tadalafil (Canadian-sourced). No clinically significant differences in PK were determined between fed and fasted conditions; the FDC formulation could be taken irrespective of meals. The FDC formulation under fasted and fed conditions was well tolerated with no clinically relevant differences in safety profiles between the treatment groups. NCT Number: NCT04235270.


Assuntos
COVID-19/epidemiologia , Jejum/sangue , Interações Alimento-Droga/fisiologia , Pirimidinas/sangue , Projetos de Pesquisa , Sulfonamidas/sangue , Tadalafila/sangue , Adulto , COVID-19/prevenção & controle , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Projetos de Pesquisa/tendências , Sulfonamidas/administração & dosagem , Tadalafila/administração & dosagem , Equivalência Terapêutica , Adulto Jovem
3.
AIDS Educ Prev ; 33(5): 361-376, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34596427

RESUMO

We triangulated quantitative and qualitative assessments to evaluate participants' acceptability of 0.05% dapivirine rectal microbicide (RM) gel administered via two separate modalities (a rectal applicator and an artificial phallus for use as a coital simulation device) as part of a Phase I trial (N = 14) among men who have sex with men (MSM) randomized using a 1:1 ratio. Overall, participants reported favorable acceptability of the gel (n = 11; 78.6%), the same or more at the end of the study compared to when they started the study. Additionally, when discussing their preferred administration modality, they noted that both methods had positive qualities but also potential areas of improvement. Our findings underscore the need to create multiple delivery methods for a future microbicide gel (i.e., with and without the need for an applicator) and highlight the importance of offering MSM choices in how biomedical HIV prevention strategies are delivered.


Assuntos
Infecções por HIV , HIV-1 , Minorias Sexuais e de Gênero , Administração Retal , Adulto , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Humanos , Masculino , Pirimidinas
4.
Molecules ; 26(19)2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34641566

RESUMO

Antimicrobial resistance was one of the top priorities for global public health before the start of the 2019 coronavirus pandemic (COVID-19). Moreover, in this changing medical landscape due to COVID-19, finding new organic structures with antimicrobial and antiviral properties is a priority in current research. The Biginelli synthesis that mediates the production of pyrimidine compounds has been intensively studied in recent decades, especially due to the therapeutic properties of the resulting compounds, such as calcium channel blockers, anticancer, antiviral, antimicrobial, anti-inflammatory or antioxidant compounds. In this review we aim to review the Biginelli syntheses reported recently in the literature that mediates the synthesis of antimicrobial compounds, the spectrum of their medicinal properties, and the structure-activity relationship in the studied compounds.


Assuntos
Anti-Infecciosos/síntese química , Pirimidinas/síntese química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Técnicas de Química Sintética/métodos , Descoberta de Drogas , Resistência Microbiana a Medicamentos , Humanos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos
5.
Nat Commun ; 12(1): 5248, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504076

RESUMO

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers.


Assuntos
Carcinogênese/genética , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Antígenos de Histocompatibilidade Menor/genética , Neoplasias Pancreáticas/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Antineoplásicos/farmacologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cães , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Células Madin Darby de Rim Canino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos SCID , Antígenos de Histocompatibilidade Menor/metabolismo , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fosfatos de Fosfatidilinositol/biossíntese , Fosfatidilserinas/biossíntese , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Commun ; 12(1): 5337, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504101

RESUMO

TNK1 is a non-receptor tyrosine kinase with poorly understood biological function and regulation. Here, we identify TNK1 dependencies in primary human cancers. We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity. Conversely, the release of TNK1 from 14-3-3 allows TNK1 to cluster in ubiquitin-rich puncta and become active. Active TNK1 induces growth factor-independent proliferation of lymphoid cells in cell culture and mouse models. One unusual feature of TNK1 is a ubiquitin-association domain (UBA) on its C-terminus. Here, we characterize the TNK1 UBA, which has high affinity for poly-ubiquitin. Point mutations that disrupt ubiquitin binding inhibit TNK1 activity. These data suggest a mechanism in which TNK1 toggles between 14-3-3-bound (inactive) and ubiquitin-bound (active) states. Finally, we identify a TNK1 inhibitor, TP-5801, which shows nanomolar potency against TNK1-transformed cells and suppresses tumor growth in vivo.


Assuntos
Proteínas 14-3-3/genética , Proteínas Fetais/genética , Linfócitos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Tirosina Quinases/genética , Ubiquitina/genética , Proteínas 14-3-3/metabolismo , Células A549 , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proteínas Fetais/antagonistas & inibidores , Proteínas Fetais/metabolismo , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Camundongos , Fosfolipase C gama/genética , Fosfolipase C gama/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/farmacologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Drugs Today (Barc) ; 57(9): 559-569, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34586104

RESUMO

The identification of oncogenic drivers and the subsequent development of targeted therapies have been established as biomarker-based care for metastatic non-small cell lung cancer (NSCLC) patients. Rearranged during transfection (RET) events have been reported to be oncogenic drivers in NSCLC and were more common in patients who i) were young; ii) had adenocarcinoma histology; and iii) had never smoked. Phase II studies indicated the limited efficacy of multi-targeted tyrosine kinase inhibitors in patients with NSCLC that have a confirmed RET event. Consequently, there has been ongoing research to develop more potent and specific RET tyrosine kinase inhibitors. Recently, a novel and specific RET inhibitor, pralsetinib (BLU-667), has been reported to have excellent efficacy and low off-target toxicity in RET cancer patients. In this review, we summarize the clinical data regarding the use of pralsetinib in NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-ret , Pirazóis , Piridinas , Pirimidinas
8.
An Acad Bras Cienc ; 93(suppl 3): e20200860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34550199

RESUMO

The use of agrochemicals in agriculture may impact aquatic ecosystems, particularly influencing the stream insect communities. Among aquatic insects, the family Chironomidae is the most abundant and species-diverse insect group found in freshwater ecosystems. However, in the southern hemisphere, studies with Chironomidae are still sparse, compared to Europe and North America. The present study evaluates the responses of Chironomidae species (Insecta: Diptera) to pyrimethanil fungicide in a mesocosm experiment. Water contamination and chironomid community were monitored over 10 months. After five months of monitoring, the pyrimethanil fungicide was completely degraded and there was a statistically significant increase in the Margalef Richness and Shannon-Wiener Index (H') in the control units when compared with the contaminated mesocosms (p = 0.003). Our results point out that the utilization of agrochemicals can be a harmful factor influencing negatively the Chironomidae populations. This finding has key implications for insect conservation strategies and ecological management environments.


Assuntos
Chironomidae , Fungicidas Industriais , Animais , Ecossistema , Fungicidas Industriais/toxicidade , Pirimidinas/toxicidade
9.
Chimia (Aarau) ; 75(7): 605-613, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34523401

RESUMO

Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Masculino , Neoplasias/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico
11.
J Org Chem ; 86(18): 12517-12527, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34468136

RESUMO

Thiazolo[4,5-d]pyrimidine is one of the purine isosteres that possesses a variety of pharmaceutical activities and is an attractive scaffold for drug discovery. In this work, a novel protocol for the synthesis of 7-aminothiazolo[4,5,-d]pyrimidine scaffold libraries on solid support has been developed using a traceless linker. Dimroth rearrangement afforded the desired intermediate with a fused heterocyclic thiazolo[4,5,-d]pyrimidine core skeleton. To diversify the synthesized library, three types of building blocks were introduced to the resin-bound thiazolo[4,5,-d]pyrimidine through N-acylation, N-alkylation, and nucleophilic substitution with amines during cleavage from the resin. The synthesized compounds were produced in seven steps with overall yields of 11-48%. Additionally, physicochemical properties, as well as drug-likeness of the library, were calculated.


Assuntos
Pirimidinas , Técnicas de Síntese em Fase Sólida , Acilação , Alquilação , Aminas
12.
J Org Chem ; 86(19): 13465-13474, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34499494

RESUMO

A comprehensive study of the reaction scope of methyl 1,2,3-triazine-5-carboxylate (3a) with alkyl and aryl amidines is disclosed, reacting at room temperature at remarkable rates (<5 min, 0.1 M in CH3CN) nearly 10000-fold faster than that of unsubstituted 1,2,3-triazine and providing the product pyrimidines in high yields. C4 Methyl substitution of the 1,2,3-triazine (3b) had little effect on the rate of the reaction, whereas C4/C6 dimethyl substitution (3c) slowed the room-temperature reaction (<24 h, 0.25 M) but displayed an unaltered scope, providing the product pyrimidines in similarly high yields. Measured second-order rate constants of the reaction of 3a-c, the corresponding nitriles 3e and 3f, and 1,2,3-triazine itself (3d) with benzamidine and substituted derivatives quantitated the remarkable reactivity of 3a and 3e, verified the inverse electron demand nature of the reaction (Hammett ρ = -1.50 for substituted amidines, ρ = +7.9 for 5-substituted 1,2,3-triazine), and provided a quantitative measure of the impact of 4-methyl and 4,6-dimethyl substitution on the reactivity of the methyl 1,2,3-triazine-5-carboxylate and 5-cyano-1,2,3-triazine core heterocycles.


Assuntos
Amidinas , Triazinas , Ácidos Carboxílicos , Elétrons , Pirimidinas
13.
J Org Chem ; 86(19): 13734-13743, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34541847

RESUMO

An efficient, facile, and eco-friendly synthesis of pyrimidine derivatives has been developed. It involves a [3 + 2 + 1] three-component annulation of amidines, ketones, and one carbon source. N,N-Dimethylaminoethanol is oxidized through C(sp3)-H activation to provide the carbon donor. One C-C and two C-N bonds are formed during the oxidative annulation process. The reaction shows good tolerance to many important functional groups in air, making this methodology a highly versatile alternative, and significant improvement to the existing methods for structuring a pyrimidine framework, especially 4-aliphatic pyrimidines.


Assuntos
Amidinas , Cetonas , Carbono , Catálise , Deanol , Pirimidinas
14.
Front Immunol ; 12: 673985, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557184

RESUMO

Reactive oxygen species (ROS) play a crucial role in the cellular defense against S. aureus, as evidenced by the importance of this pathogen in patients lacking the ROS-generating phagocyte NADPH oxidase NOX2. ROS concentrations required to kill S. aureus in vitro are much higher than those found in the phagosome. We therefore hypothesized that sublethal ROS concentrations may play a role in S. aureus gene dysregulation and investigated the in vitro transcriptomic response of S. aureus to sublethal concentrations of hydrogen peroxide (H2O2). A striking observation of these experiments was a coordinated and massive downregulation of genes involved in pyrimidine metabolism. Using transposon insertion mutants, we demonstrated that deletion of carA, a gene involved in pyrimidine synthesis, led to a significant growth defect and to an increased sensitivity of S. aureus to added H2O2. The phenotype of the carA mutant could be reversed through supplementation with the pyrimidine precursor uracil, or with a multicopy vector encoding carA. As opposed to the impact of ROS on extracellular survival, carA deletion did not affect the intracellular survival in neutrophils. Our results raise the possibility that ROS-dependent downregulation of pyrimidine metabolism might be a survival strategy of S. aureus, allowing colonization through intracellular survival, while decreasing the risk of killing the host through dampened extracellular growth.


Assuntos
Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Pirimidinas/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Proteínas de Bactérias/metabolismo , Células Cultivadas , Regulação para Baixo , Humanos , Neutrófilos/microbiologia , Espécies Reativas de Oxigênio/metabolismo
15.
J Phys Chem B ; 125(36): 10072-10084, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34473499

RESUMO

The phosphatidylinostitol-3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is a vital regulator of cell proliferation, growth, and survival, which is frequently overactivated in many human cancers. To this effect, PI3K, which is an important mediator of this pathway, has been pinpointed as a crucial target in cancer therapy and hence the importance of PI3K inhibitors. It was recently reported that defluorination and pyridine-to-pyrimidine ring interconversion increase the potency of specific small-molecule inhibitors of PI3K. Compound 4, an inhibitor with the difluorinated pyrimidine motif, was found to be eight times more potent against PI3K than compound 1, an inhibitor with the trifluorinated pyridine motif. This observation presents the need to rationally resolve the differential inhibitory mechanisms exhibited by both compounds. In this present work, we employed multiple computational approaches to investigate and distinguish the binding modes of 1 and 4 in addition to the effects they mediate on the secondary structure of PI3K. Likewise, we evaluated two other derivatives, compounds 2 with the difluorinated pyridine motif and 3 with the trifluorinated pyrimidine motif, to investigate the cooperativity effect between the defluorination of CF3 and pyridine-to-pyrimidine ring interconversion. Findings revealed that PI3K, upon interaction with 4, exhibited a series of structural changes that favored the binding of the inhibitor at the active-site region. Furthermore, a positive (synergistic) cooperativity effect was observed between CF3 defluorination and pyridine-to-pyrimidine ring interconversion. Moreover, there was a good correlation between the binding free energy estimated and the biological activity reported experimentally. Energy decomposition analysis revealed that the major contributing force to binding affinity variations between 1 and 4 is the electrostatic energy. Per-residue energy-based hierarchical clustering analysis further identified four hot-spot residues ASP841, TYR867, ASP964, and LYS833 and four warm-spot residues ASP836, SER806, ASP837, and LYS808, which essentially mediate the optimal and higher-affinity binding of compound 4 to PI3K relative to 1. This study therefore provides rational insights into the mechanisms by which 4 exhibited superior PI3K-inhibitory activities over 1, which is vital for future structure-based drug discovery efforts in PI3K targeting.


Assuntos
Fosfatidilinositol 3-Quinases , Triazinas , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
16.
Front Immunol ; 12: 661323, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531850

RESUMO

Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1ß drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL-6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1ß specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1ß/IL-6/STAT3 axis, we suppressed IL-1ß-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor. In vivo, using B16F10 melanoma, OLT1177 effectively reduced tumor progression (p< 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% (p<0.01) and II6 expression by 53% (p<0.05). Disruption of tumor-derived NLRP3, either pharmacologically or genetically, reduced STAT3 signaling in bone marrow cells. In PMN-MDSCs isolated from tumor-bearing mice treated with OLT1177, we observed significant reductions in immunosuppressive genes such as Pdcd1l1, Arg1, Il10 and Tgfb1. In conclusion, the data presented here show that the inhibition of NLRP3 reduces IL-1ß induction of pSTAT3(Y705) preventing expression of immunosuppressive genes as well as activity in PMN-MDSCs.


Assuntos
Interleucina-1beta/imunologia , Interleucina-6/imunologia , Melanoma/imunologia , Células Supressoras Mieloides/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fator de Transcrição STAT3/imunologia , Animais , Linhagem Celular Tumoral , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Células Supressoras Mieloides/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nitrilas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
17.
BMC Cancer ; 21(1): 1021, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521387

RESUMO

BACKGROUND: Clinical effectiveness and safety data of pazopanib in patients with advanced or mRCC in real-world setting from Asia Pacific, North Africa, and Middle East countries are lacking. METHODS: PARACHUTE is a phase IV, prospective, non-interventional, observational study. Primary endpoint was the proportion of patients remaining progression free at 12 months. Secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI). RESULTS: Overall, 190 patients with a median age of 61 years (range: 22.0-96.0) were included. Most patients were Asian (70%), clear-cell type RCC was the most common (81%), with a favourable (9%), intermediate (47%), poor (10%), and unknown (34%) MSKCC risk score. At the end of the observational period, 78 patients completed the observational period and 112 discontinued the study; 60% of patients had the starting dose at 800 mg. Median RDI was 82%, with 52% of patients receiving < 85%. Of the 145 evaluable patients, 56 (39%) remained progression free at 12 months, and the median PFS was 10 months (95% CI: 8.48-11.83). 19% of patients (21/109) were long-term responders (on pazopanib for ≥18 months). The best response per RECIST 1.1 was CR/PR in 24%, stable disease in 44%, and PD in 31%. Most frequent (> 10%) TEAEs related to pazopanib included diarrhoea (30%), palmar-plantar erythrodysesthesia syndrome (15%), and hypertension (14%). CONCLUSIONS: Results of the PARACHUTE study support the use of pazopanib in patients with advanced or mRCC who are naive to VEGF-TKI therapy. The safety profile is consistent with that previously reported by pivotal and real-world evidence studies.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , África do Norte , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Ásia , Carcinoma de Células Renais/etnologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Neoplasias Renais/etnologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Oriente Médio , Intervalo Livre de Progressão , Estudos Prospectivos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Fatores de Risco , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
18.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500625

RESUMO

The photophysical relaxation mechanisms of 1-cyclohexyluracil, in vacuum and water, were investigated by employing the Multi-State CASPT2 (MS-CASPT2, Multi-State Complete Active-Space Second-Order Perturbation Theory) quantum chemical method and Dunning's cc-pVDZ basis sets. In both environments, our results suggest that the primary photophysical event is the population of the S11(ππ*) bright state. Afterwards, two likely deactivation pathways can take place, which is sustained by linear interpolation in internal coordinates defined via Z-Matrix scans connecting the most important characteristic points. The first one (Route 1) is the same relaxation mechanism observed for uracil, its canonical analogue, i.e., internal conversion to the ground state through an ethylenic-like conical intersection. The other route (Route 2) is the direct population transfer from the S11(ππ*) bright state to the T23(nπ*) triplet state via an intersystem crossing process involving the (S11(ππ*)/T23(nπ*))STCP singlet-triplet crossing point. As the spin-orbit coupling is not too large in either environment, we propose that most of the electronic population initially on the S11(ππ*) state returns to the ground following the same ultrafast deactivation mechanism observed in uracil (Route 1), while a smaller percentage goes to the triplet manifold. The presence of a minimum on the S11(ππ*) potential energy hypersurface in water can help to understand why experimentally it is noticed suppression of the triplet states population in polar protic solvent.


Assuntos
Pirimidinas/química , Uracila/análogos & derivados , Teoria Quântica , Solventes/química , Termodinâmica , Uracila/química , Água/química
19.
BMJ Case Rep ; 14(9)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479888

RESUMO

Nilotinib is used as standard treatment in managing chronic myeloid leukaemia (CML). A 23-year-old man with CML and on nilotinib was admitted to the intensive care unit due to respiratory failure. Three years prior, he developed pleural effusion from dasatinib therapy thus, his CML regimen was changed to nilotinib. Although the pleural effusion had once improved, the chest imaging revealed left-dominant bilateral pleural effusion. Endotracheal intubation and left thoracic drainage were performed. Nilotinib treatment was discontinued, and approximately 60 hours later, nilotinib concentrations of 927 and 2092 ng/mL were determined in his blood and pleural effusion, respectively. Severe pleural effusion may be induced in patients administering nilotinib, and nilotinib concentrations in blood and pleural effusion can be elevated in patients with nilotinib-related pleural effusion. Cross-occurrence of pleural effusions needs to be monitored precisely, especially in patients who are switched to other tyrosine kinase inhibitors after dasatinib treatment.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Derrame Pleural , Adulto , Antineoplásicos/efeitos adversos , Dasatinibe/efeitos adversos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Derrame Pleural/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas , Adulto Jovem
20.
Nat Commun ; 12(1): 5492, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535643

RESUMO

Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by stimulators and activators. However, the detailed structural mechanisms, through which sGC is recognized and positively modulated by these drugs at high spacial resolution, are poorly understood. Here, we present cryo-electron microscopy structures of human sGC in complex with NO and sGC stimulators, YC-1 and riociguat, and also in complex with the activator cinaciguat. These structures uncover the molecular details of how stimulators interact with residues from both ß H-NOX and CC domains, to stabilize sGC in the extended active conformation. In contrast, cinaciguat occupies the haem pocket in the ß H-NOX domain and sGC shows both inactive and active conformations. These structures suggest a converged mechanism of sGC activation by pharmacological compounds.


Assuntos
Ativadores de Enzimas/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Animais , Benzoatos/química , Benzoatos/farmacologia , Sítios de Ligação , Linhagem Celular , Microscopia Crioeletrônica , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/química , Humanos , Indazóis/química , Indazóis/farmacologia , Modelos Moleculares , Óxido Nítrico/farmacologia , Multimerização Proteica , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Guanilil Ciclase Solúvel/química , Guanilil Ciclase Solúvel/ultraestrutura
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