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1.
J Chem Inf Model ; 61(10): 5256-5268, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34597510

RESUMO

African and American trypanosomiases are estimated to affect several million people across the world, with effective treatments distinctly lacking. New, ideally oral, treatments with higher efficacy against these diseases are desperately needed. Peroxisomal import matrix (PEX) proteins represent a very interesting target for structure- and ligand-based drug design. The PEX5-PEX14 protein-protein interface in particular has been highlighted as a target, with inhibitors shown to disrupt essential cell processes in trypanosomes, leading to cell death. In this work, we present a drug development campaign that utilizes the synergy between structural biology, computer-aided drug design, and medicinal chemistry in the quest to discover and develop new potential compounds to treat trypanosomiasis by targeting the PEX14-PEX5 interaction. Using the structure of the known lead compounds discovered by Dawidowski et al. as the template for a chemically advanced template search (CATS) algorithm, we performed scaffold-hopping to obtain a new class of compounds with trypanocidal activity, based on 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines chemistry. The initial compounds obtained were taken forward to a first round of hit-to-lead optimization by synthesis of derivatives, which show activities in the range of low- to high-digit micromolar IC50 in the in vitro tests. The NMR measurements confirm binding to PEX14 in solution, while immunofluorescent microscopy indicates disruption of protein import into the glycosomes, indicating that the PEX14-PEX5 protein-protein interface was successfully disrupted. These studies result in development of a novel scaffold for future lead optimization, while ADME testing gives an indication of further areas of improvement in the path from lead molecules toward a new drug active against trypanosomes.


Assuntos
Oxazepinas , Tripanossomicidas , Desenho Assistido por Computador , Proteínas de Membrana/metabolismo , Receptor 1 de Sinal de Orientação para Peroxissomos , Receptores Citoplasmáticos e Nucleares , Proteínas Repressoras/metabolismo , Tripanossomicidas/farmacologia
2.
Nanomedicine (Lond) ; 16(23): 2095-2115, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34523353

RESUMO

Aim: To develop and characterize bozepinib-loaded lipid-core nanocapsules (BZP-LNC+) as a potential treatment for glioblastoma (GBM). Methods: Characterization of nanocapsules was performed by diameter, polydispersity index, Zeta potential, pH and encapsulation efficiency. GBM cell viability, cell cycle and Annexin/PI were evaluated after BZP-LNC+ treatment. Synergism between BZP-LNC+ and temozolomide (TMZ) was performed by CompuSyn software and confirmed in vitro and in vivo. Results: BZP-LNC+ showed adequate particle sizes, positive Zeta potential, narrow size distribution and high encapsulation efficiency. BZP-LNC+ reduces GBM growth by inducing apoptosis. BZP-LNC+ and TMZ showed synergistic effect in vitro and reduced the in vivo glioma growth by approximately 81%. Conclusion: The present study provides proof-of-principle insights for the combination of these drugs for GBM treatment.


Assuntos
Glioblastoma , Nanocápsulas , Encéfalo , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Nanocápsulas/uso terapêutico , Oxazepinas , Purinas
3.
J Org Chem ; 86(9): 6289-6304, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33872009

RESUMO

A one-pot two-step protocol for the synthesis of 2-acetyl-1H-pyrroles from N-propargylic ß-enaminones was described. When treated with zinc chloride in refluxing chloroform, N-propargylic ß-enaminones produced in situ 2-methylene-2,3-dihydro-1,4-oxazepines, which, upon further refluxing in methanol with zinc chloride, afforded 2-acetyl-1H-pyrroles. The process was found to be general for a wide variety of N-propargylic ß-enaminones and yielded a diverse range of 2-acetyl-1H-pyrroles in good to high yields with large substrate scope and good functional group tolerance. This operationally easy method may provide a rapid access to functionalized 2-acetyl-1H-pyrroles of pharmacological interest.


Assuntos
Oxazepinas , Pirróis
4.
Eur J Med Chem ; 220: 113484, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33930803

RESUMO

Necroptosis is reported to play a critical role in contributing to a variety of human pathologies. The benzoxazepinone GSK'772 is a potent necroptosis inhibitor optimized using a hit from a DNA-encoded library, which is currently in phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. In the present study, the bioisosterism strategy was applied to replace the amide and benzene ring of GSK'772 based on the co-crystal structure of GSK'772 with its binding target RIPK1. As a result, the novel thio-benzoxazepinones exhibited higher anti-necroptosis activity in a human HT-29 cell necroptosis model. The effect on anti-necroptosis activity by the chirality was significantly reduced in the thio-benzoxazepinones, which was explained by the ligand conformation calculation. Among these analogues, compound 11 (S) and 12 (R) specifically inhibited necroptosis rather than apoptosis with EC50 values of 2.8 and 22.6 nM. They blocked necrosome formation by inhibiting the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. Collectively, the highly potent thio-benzoxazepinones represent promising lead structures for further development of necroptosis-related diseases.


Assuntos
Desenho de Fármacos , Necroptose/efeitos dos fármacos , Oxazepinas/farmacologia , Compostos de Sulfidrila/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Oxazepinas/síntese química , Oxazepinas/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Células Tumorais Cultivadas
5.
Arthritis Res Ther ; 23(1): 85, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726834

RESUMO

BACKGROUND: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). METHODS: Patients with moderate to severe RA who had received ≥12 weeks' stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. RESULTS: A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints-C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. CONCLUSIONS: These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.


Assuntos
Antirreumáticos , Artrite Reumatoide , Pesquisa Biomédica , Oxazepinas , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Método Duplo-Cego , Humanos , Oxazepinas/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores , Resultado do Tratamento , Triazóis
6.
Eur J Pharm Sci ; 162: 105823, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33781855

RESUMO

Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults and the current treatments only have a modest effect on patient survival. Recent studies show that bozepinib (BZP), a purine derivative, has potential applications in cancer treatment. The aim of this study was to evaluate the effect of BZP against GBM cells, specially concerning the purinergic system. Thus, GBM cells (C6 and U138 cell lines) were treated with BZP and cell viability, cell cycle, and annexin/PI assays, and active caspase-3 measurements were carried out. Besides, the effect of BZP over the purinergic system was also evaluated in silico and in vitro. Finally, we evaluate the action of BZP against important markers related to cancer progression, such as Akt, NF-κB, and CD133. We demonstrate here that BZP reduces GBM cell viability (IC50 = 5.7 ± 0.3 µM and 12.7 ± 1.5 µM, in C6 and U138 cells, respectively), inducing cell death through caspase-dependent apoptosis, autophagosome formation, activation of NF-κB, without any change in cell cycle progression or on the Akt pathway. Also, BZP modulates the purinergic system, inducing an increase in CD39 enzyme expression and activity, while inhibiting CD73 activity and adenosine formation, without altering CD73 enzyme expression. Curiously, one cycle of treatment resulted in enrichment of GBM cells expressing NF-κB and CD133+, suggesting resistant cells selection. However, after another treatment round, the resistant cells were eliminated. Altogether, BZP presented in vitro anti-glioma activity, encouraging further in vivo studies in order to better understand its mechanism of action.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Oxazepinas , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Glioblastoma/tratamento farmacológico , Humanos , Purinas
7.
Bioorg Med Chem ; 34: 116015, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33549905

RESUMO

Bromodomain and extra-terminal domain (BET) protein plays an important role in epigenetic regulation, and the regulation of disruption contributes to the pathogenesis of cancer and inflammatory disease. With the goal of discovering novel BET inhibitors, especially BRD4 inhibitors, we designed and synthesized several compounds starting from our previously reported pyrido-benzodiazepinone derivative 4 to enhance BRD4 inhibitory activity while avoiding hERG inhibition. Molecular docking studies and structure-activity relationship studies led to the identification of 9-fluorobenzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivative 43, which exhibited potent BRD4 inhibitory activity with excellent potency in imiquimod-induced psoriasis model mice.


Assuntos
Proteínas do Tecido Nervoso/antagonistas & inibidores , Oxazepinas/química , Oxazepinas/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Modelos Moleculares , Estrutura Molecular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/classificação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oxazepinas/administração & dosagem , Oxazepinas/síntese química , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/classificação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
Eur J Drug Metab Pharmacokinet ; 46(1): 71-83, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33165774

RESUMO

BACKGROUND AND OBJECTIVES: GSK2982772 is an oral small-molecule RIPK1 inhibitor with potential therapeutic efficacy in immune-mediated inflammatory diseases (IMIDs). An inter-ethnic comparison of GSK2982772 pharmacokinetics was conducted based on data from Western (Study 1) and Japanese subjects (Study 2). METHODS: Both studies were single-centre, randomised, double-blind, placebo-controlled studies with objectives to assess the safety and characterise the pharmacokinetics of GSK2982772. Western subjects in Study 1 (NCT03305419), Part A (N = 15), were randomly assigned to receive 120 mg three times daily (TID), 240 mg TID, or 360 mg twice daily (BID) doses of GSK2982772, or placebo (TID or BID) for 1 day. Part B subjects (N = 47) received GSK2982772 120 mg TID, 240 mg TID, or placebo TID for 14 days. Japanese subjects in Study 2 (N = 13) (NCT03590613) were randomly assigned to receive TID doses of GSK2982772 60, 120, 240 mg TID or placebo TID for 1 day. RESULTS: GSK2982772 was well tolerated and adverse events were generally mild. Maximum observed plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma drug concentration versus time curve after the first GSK2982772 dose (AUC(0-7)) of 120 and 240 mg, and (AUC(0-24)) values for the 120 and 240 mg TID doses over a single day were similar in Japanese and Western subjects. CONCLUSIONS: The pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs. Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov .


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Europeu/etnologia , Voluntários Saudáveis , Oxazepinas/sangue , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Triazóis/sangue , Adulto , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Japão/etnologia , Masculino , Pessoa de Meia-Idade , Oxazepinas/administração & dosagem , Oxazepinas/farmacocinética , Triazóis/administração & dosagem , Triazóis/farmacocinética , Reino Unido/etnologia
9.
Ann Oncol ; 32(2): 197-207, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33186740

RESUMO

BACKGROUND: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. RESULTS: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. CONCLUSION: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Fulvestranto , Humanos , Imidazóis , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Oxazepinas , Fosfatidilinositol 3-Quinases , Qualidade de Vida , Receptor ErbB-2/genética
11.
Cancer Discov ; 11(1): 92-107, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32958578

RESUMO

Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA-mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA-mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8-59.4]. Durable disease control was observed in PIK3CA-mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3-13.1; P = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4-19.4; P = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy. SIGNIFICANCE: The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated PIK3CA-mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with PIK3CA-mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Fulvestranto , Humanos , Imidazóis , Oxazepinas , Fosfatidilinositol 3-Quinases , Piperazinas , Piridinas , Receptor ErbB-2/genética
12.
Mol Divers ; 25(1): 159-169, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31965437

RESUMO

Nitrogen- or oxygen-containing organic compounds which have significant antifungal activity, twenty one novel nitrogen or oxygen-containing (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR and HRMS. Preliminary bioassay showed that most of them exhibited certain-to-good antifungal activity. Compounds 5k-2, 5n, 5p and 5r exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 µg/mL, and 5r exhibited good antifungal activity against S. sclerotiorum with EC50 of 7.21 µg/mL. Compounds 5a and 5r also showed over 90% inhibition against Botrytis cinerea. In particular, 5r showed significant higher activity with the lowest EC50 of 7.92 µg/mL than the positive control trifloxystrobin (21.96 µg/mL) and azoxystrobin (9.43 µg/mL). Providing a practical method for the synthesis of new scaffolds 1,2-Benzoxazepinone and systematically investigate their antifungal activity.


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Oxazepinas/síntese química , Oxazepinas/farmacologia , Acetatos/farmacologia , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Iminas/farmacologia , Nitrogênio/química , Oxigênio/química , Pirimidinas/farmacologia , Estrobilurinas/farmacologia
13.
N Engl J Med ; 383(22): 2127-2137, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-32897034

RESUMO

BACKGROUND: Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. METHODS: In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed. RESULTS: Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo. CONCLUSIONS: In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).


Assuntos
Benzoxazóis/administração & dosagem , Bronquiectasia/tratamento farmacológico , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Oxazepinas/administração & dosagem , Serina Proteases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoxazóis/efeitos adversos , Bronquiectasia/metabolismo , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Elastase de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Oxazepinas/efeitos adversos , Escarro/metabolismo
14.
Mol Pharmacol ; 98(5): 540-547, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32938719

RESUMO

GS-967 and eleclazine (GS-6615) are novel sodium channel inhibitors exhibiting antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current (I NaL). Here, we took advantage of a high throughput automated electrophysiology platform (SyncroPatch 768PE) to investigate the molecular pharmacology of GS-967 and eleclazine on peak sodium current (I NaP) recorded from human induced pluripotent stem cell-derived cardiomyocytes. We compared the effects of GS-967 and eleclazine with the antiarrhythmic drug lidocaine, the prototype I NaL inhibitor ranolazine, and the slow inactivation enhancing drug lacosamide. In human induced pluripotent stem cell-derived cardiomyocytes, GS-967 and eleclazine caused a reduction of I NaP in a frequency-dependent manner consistent with use-dependent block (UDB). GS-967 and eleclazine had similar efficacy but evoked more potent UDB of I NaP (IC50 = 0.07 and 0.6 µM, respectively) than ranolazine (7.8 µM), lidocaine (133.5 µM), and lacosamide (158.5 µM). In addition, GS-967 and eleclazine exerted more potent effects on slow inactivation and recovery from inactivation compared with the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the higher association rates and moderate unbinding rate of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine. SIGNIFICANCE STATEMENT: We investigated the molecular pharmacology of GS-967 and eleclazine on sodium channels in human induced pluripotent stem cell-derived cardiomyocytes using a high throughput automated electrophysiology platform. Sodium channel inhibition by GS-967 and eleclazine has unique effects, including accelerating the onset of slow inactivation and impairing recovery from inactivation. These effects combined with rapid binding and moderate unbinding kinetics explain potent use-dependent block, which we propose contributes to their observed antiarrhythmic efficacy.


Assuntos
Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Oxazepinas/farmacologia , Piridinas/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Triazóis/farmacologia , Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Células Cultivadas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Lidocaína/farmacologia , Miócitos Cardíacos/metabolismo , Ranolazina/farmacologia
15.
Cancer Cell ; 38(4): 516-533.e9, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-32976773

RESUMO

PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized 13C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[18F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Proteína Forkhead Box M1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Proteína Forkhead Box M1/genética , Fulvestranto/administração & dosagem , Humanos , Imidazóis/administração & dosagem , Células MCF-7 , Imageamento por Ressonância Magnética/métodos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Oxazepinas/administração & dosagem , Receptores de Estrogênio/metabolismo , Tamoxifeno/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Mol Reprod Dev ; 87(9): 1009-1017, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32818292

RESUMO

Cell cycle of mouse embryo could be delayed by nicotinamide (NAM). Histone H3 lysine 56 (H3K56ac) acetylation plays an important role in mammalian genomic stability and the function of this modification in mouse embryos is not known. Hence, we designed to study the effects of NAM-induced oxidative stress on the developmental ability of mouse embryos, on the acetylation of H3K56ac and the possible functions of this modification related to mouse embryo development. Treatment with NAM (10, 20, or 40 mmol/L for 24 or 48 hr) during in vitro culture significantly decreased developmental rate of blastocyst (24 hr: 90.2 vs. 81.2, 43.2, and 18.2, with p > .05, p < .01, respectively; 48 hr: 89.3 vs. 53.2%, 12.1%, and 0% with p < .05, respectively). NAM treatment (20 mmol/L) for 6 and 31 hr resulted in increased intracellular reactive oxygen species levels in two-cell embryos, and apoptotic cell numbers in blastocysts. Resveratrol (RSV) and I-CBP112 rescued the 20 mmol/L NAM-induced embryo developmental defects. RSV and I-CBP112 increased the level of Sirt1 and decreased the level of H3K56ac induced by NAM in two-cell embryos (p < .05). These data suggest that NAM treatment decreases the expression of Sirt1, which induces high levels of H3K56 acetylation that may be involved in oxidative stress-induced mouse embryo defects, which can be rescued by RSV and I-CBP112.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Niacinamida/farmacologia , Oxazepinas/farmacologia , Piperidinas/farmacologia , Resveratrol/farmacologia , Animais , Células Cultivadas , Citoproteção/efeitos dos fármacos , Citoproteção/genética , Técnicas de Cultura Embrionária , Embrião de Mamíferos/citologia , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histonas/efeitos dos fármacos , Histonas/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo
17.
J Dermatol Sci ; 99(3): 146-151, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32600738

RESUMO

Skin diseases bring great psychological and physical impacts on patients, however, a considerable number of skin diseases still lack effective treatments, such as psoriasis, systemic lupus erythematosus, melanoma and so on. Receptor-interacting serine threonine kinase 1 (RIPK1) plays an important role in cell death, especially necroptosis, associated with inflammation and tumor. As many molecules modulate the ubiquitination of RIPK1, disruption of this checkpoint can lead to skin diseases, which can be ameliorated by RIPK1 inhibitors. This review will focus on the molecular mechanism of RIPK1 activation in inflammation as well as the current knowledges on the contribution of RIPK1 in skin diseases.


Assuntos
Dermatite/imunologia , Necroptose/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Neoplasias Cutâneas/imunologia , Animais , Ensaios Clínicos Fase II como Assunto , Dermatite/tratamento farmacológico , Dermatite/genética , Dermatite/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Imidazóis/farmacologia , Indóis/farmacologia , Camundongos , Camundongos Knockout , Necroptose/efeitos dos fármacos , Necroptose/genética , Oxazepinas/farmacologia , Oxazepinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Ratos , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Triazóis/farmacologia , Triazóis/uso terapêutico , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Ubiquitinação/imunologia
18.
ChemMedChem ; 15(16): 1571-1578, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32485077

RESUMO

In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC50 value of 1 µM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5 nM in HCT116 and K562 cells. Molecular modeling studies perfectly corroborates these promising results.


Assuntos
Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Oxazepinas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Oxazepinas/síntese química , Oxazepinas/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Células Tumorais Cultivadas
19.
Eur J Med Chem ; 201: 112443, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32599324

RESUMO

CDK8 is a cyclin-dependent kinase that forms part of the mediator complex, and modulates the transcriptional output from distinct transcription factors involved in oncogenic control. Overexpression of CDK8 has been observed in various cancers, representing a potential target for developing novel CDK8 inhibitors in cancer therapeutics. In the course of our investigations to discover new CDK8 inhibitors, we designed and synthesized tricyclic pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives, by introduction of chemical complexity in the multi-kinase inhibitor Sorafenib taking into account the flexibility of the P-loop motif of CDK8 protein observed after analysis of structural information of co-crystallized CDK8 inhibitors. In vitro evaluation of the inhibitory activity of the prepared compounds against CDK8 led us to identify compound 2 as the most potent inhibitor of the series (IC50 = 8.25 nM). Co-crystal studies and the remarkable selectivity profile of compound 2 are presented. Compound 2 showed moderate reduction of phosphorylation of CDK8 substrate STAT1 in cells, in line with other reported Type II CDK8 inhibitors. We propose herein an alternative to find a potential therapeutic use for this chemical series.


Assuntos
Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Oxazepinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Sorafenibe/análogos & derivados , Sorafenibe/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Estrutura Molecular , Oxazepinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Relação Estrutura-Atividade
20.
ACS Comb Sci ; 22(7): 356-360, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32441919

RESUMO

Physicochemical property switching of chemical space is of great importance for optimization of compounds, for example, for biological activity. Cyclization is a key method to control 3D and other properties. A two-step approach, which involves a multicomponent reaction followed by cyclization, is reported to achieve the transition from basic moieties to charge neutral cyclic derivatives. A series of multisubstituted oxazolidinones, oxazinanones, and oxazepanones as well as their thio and sulfur derivatives are synthesized from readily available building blocks with mild conditions and high yields. Like a few other methods, MCR and cyclization allow for the collective transformation of a large chemical space into a related one with different properties.


Assuntos
Oxazepinas/síntese química , Oxazinas/síntese química , Oxazolidinonas/síntese química , Compostos de Sulfidrila/síntese química , Ciclização , Estrutura Molecular , Oxazepinas/química , Oxazinas/química , Oxazolidinonas/química , Compostos de Sulfidrila/química
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