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1.
Biomolecules ; 11(9)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34572579

RESUMO

SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease Mpro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential Mpro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 Mpro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards Mpro, with an IC50 values range of 0.36-0.89 µM comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent Mpro inhibitors.


Assuntos
Proteases 3C de Coronavírus , Inibidores de Cisteína Proteinase , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Penicillium/química , SARS-CoV-2/enzimologia , Benzodiazepinonas/química , Benzodiazepinonas/isolamento & purificação , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/isolamento & purificação
3.
Front Cell Infect Microbiol ; 11: 686035, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350133

RESUMO

The failure of highly active antiretroviral therapy (HAART) has been largely responsible for the existence of latent human immunodeficiency virus type 1 (HIV-1) reservoirs. The "shock and kill" strategy was confirmed to reactivate HIV-1 latent reservoirs by latency-reversing agents (LRAs) for accelerated HIV-1 clearance. However, a single LRA might be insufficient to induce HIV-1 reactivation from latency due to the complexity of the multiple signaling regulatory pathways that establish the HIV-1 latent reservoir. Therefore, combinations of LRAs or dual-mechanism LRAs are urgently needed to purge the latent reservoirs. We demonstrate here for the first time that a dual-target inhibitor with a specific suppressive effect on both BRD4 and TIP60, CPI-637, could reactivate latent HIV-1 in vitro by permitting Tat to bind positive transcription elongation factor b (P-TEFb) and assembling Tat-super-elongation complex (SEC) formation. In addition, CPI-637-mediated TIP60 downregulation further stimulated BRD4 dissociation from the HIV-1 long terminal repeat (LTR) promoter, allowing Tat to more effectively bind P-TEFb compared to BRD4 inhibition alone. Much more importantly, CPI-637 exerted a potent synergistic effect but alleviated global T cell activation and blocked viral spread to uninfected bystander CD4+ T cells with minimal cytotoxicity. Our results indicate that CPI-637 opens up the prospect of novel dual-target inhibitors for antagonizing HIV-1 latency and deserves further investigation for development as a promising LRA with a "shock and kill" strategy.


Assuntos
Benzodiazepinonas/farmacologia , Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos , Proteínas de Ciclo Celular/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , Humanos , Lisina Acetiltransferase 5/antagonistas & inibidores , Proteínas Nucleares , Fatores de Transcrição/antagonistas & inibidores , Ativação Viral , Latência Viral
5.
J Thorac Oncol ; 16(9): 1582-1588, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34242790

RESUMO

INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC. METHODS: One cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); Rova-T induction (0.3 mg/kg, q6 wk × 2) followed by CE every 21 days (q21) × 4 (cohort 2; n = 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk × 2) overlapping with CE q21 × 4 (cohort 3; n = 14); and Rova-T maintenance (0.3 mg/kg, q6 wk × 2) after CE q21 × 4 (cohort 4; n = 3). RESULTS: A total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had confirmed objective responses, with a median progression-free survival of 5.2 months and median overall survival of 10.3 months. Compared with cohorts 1, 2, and 4 combined, cohort 3 had lower frequency of some Rova-T-related adverse events of special interest, such as pleural effusion (0 versus 33%), pericardial effusion (0 versus 17%), ascites (0 versus 8%), peripheral edema (36% versus 42%), generalized edema (0 versus 8%), pneumonia (7% versus 25%), and hypoalbuminemia (0 versus 17%). CONCLUSIONS: Lower Rova-T doses may be associated with lower incidence of some Rova-T-related adverse events of special interest. Rova-T 0.2 mg/kg plus CE (cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE.


Assuntos
Imunoconjugados , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzodiazepinonas/uso terapêutico , Carboplatina/uso terapêutico , Etoposídeo/uso terapêutico , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
6.
J Med Chem ; 64(14): 10102-10123, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34255515

RESUMO

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.


Assuntos
Benzodiazepinonas/farmacologia , Proteína de Ligação a CREB/antagonistas & inibidores , Desenho de Fármacos , Proteína p300 Associada a E1A/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Benzodiazepinonas/síntese química , Benzodiazepinonas/química , Proteína de Ligação a CREB/metabolismo , Relação Dose-Resposta a Droga , Proteína p300 Associada a E1A/metabolismo , Células HCT116 , Humanos , Ligantes , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
7.
Cancer Sci ; 112(8): 2984-2992, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34107132

RESUMO

Delta-like canonical Notch ligand 3 (DLL3) is a member of the Delta/Serrate/Lag2 (DSL) Notch receptor ligand family and plays a crucial role in Notch signaling, which influences various cellular processes including differentiation, proliferation, survival, and apoptosis. DLL3 is expressed throughout the presomitic mesoderm and is localized to the rostral somatic compartments; mutations in DLL3 induce skeletal abnormalities such as spondylocostal dysostosis. Recently, DLL3 has attracted interest as a novel molecular target due to its high expression in neuroendocrine carcinoma of the lung. Moreover, a DLL3-targeting Ab-drug conjugate, rovalpituzumab tesirine (ROVA-T), has been developed as a new treatment with proven antitumor activity. However, the development of ROVA-T was suspended because of shorter overall survival compared to topotecan, the second-line standard treatment. Thus, several studies on the mechanism and function of DLL3 in several malignancies are underway to find a new strategy for targeting DLL3. In this review, we discuss the roles of DLL3 in various malignancies and the future perspectives of DLL3-related research, especially as a therapeutic target.


Assuntos
Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Benzodiazepinonas/farmacologia , Benzodiazepinonas/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Masculino , Proteínas de Membrana/efeitos dos fármacos , Terapia de Alvo Molecular , Mutação , Neoplasias/genética
8.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799869

RESUMO

The possible cardioprotective effects of translocator protein (TSPO) modulation with its ligand 4'-Chlorodiazepam (4'-ClDzp) in isoprenaline (ISO)-induced rat myocardial infarction (MI) were evaluated, alone or in the presence of L-NAME. Wistar albino male rats (b.w. 200-250 g, age 6-8 weeks) were divided into 4 groups (10 per group, total number N = 40), and certain substances were applied: 1. ISO 85 mg/kg b.w. (twice), 2. ISO 85 mg/kg b.w. (twice) + L-NAME 50 mg/kg b.w., 3. ISO 85 mg/kg b.w. (twice) + 4'-ClDzp 0.5 mg/kg b.w., 4. ISO 85 mg/kg b.w. (twice) + 4'-ClDzp 0.5 mg/kg b.w. + L-NAME 50 mg/kg b.w. Blood and cardiac tissue were sampled for myocardial injury and other biochemical markers, cardiac oxidative stress, and for histopathological evaluation. The reduction of serum levels of high-sensitive cardiac troponin T hs cTnT and tumor necrosis factor alpha (TNF-α), then significantly decreased levels of serum homocysteine Hcy, urea, and creatinine, and decreased levels of myocardial injury enzymes activities superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as lower grades of cardiac ischemic changes were demonstrated in ISO-induced MI treated with 4'-ClDzp. It has been detected that co-treatment with 4'-ClDzp + L-NAME changed the number of registered parameters in comparison to 4'-ClDzp group, indicating that NO (nitric oxide) should be important in the effects of 4'-ClDzp.


Assuntos
Benzodiazepinonas/farmacologia , Proteínas de Transporte/metabolismo , Infarto do Miocárdio/prevenção & controle , NG-Nitroarginina Metil Éster/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Inibidores Enzimáticos/farmacologia , Glutationa Peroxidase/metabolismo , Homocisteína/sangue , Isoproterenol , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Miocárdio/enzimologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Ratos Wistar , Superóxido Dismutase/metabolismo , Troponina T/sangue , Fator de Necrose Tumoral alfa/sangue
9.
J Thorac Oncol ; 16(9): 1570-1581, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33823285

RESUMO

INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy. METHODS: MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors. RESULTS: Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p < 0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%). CONCLUSIONS: Because of the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early. As a result, the Central Radiographic Assessment Committee evaluation of PFS was not performed. The frequency of grade greater than or equal to 3 and drug-related toxicities were higher with Rova-T versus placebo. Rova-T was associated with unique toxicities, such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the population with extensive-stage-SCLC.


Assuntos
Imunoconjugados , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzodiazepinonas/uso terapêutico , Método Duplo-Cego , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Platina/uso terapêutico
10.
J Thorac Oncol ; 16(9): 1559-1569, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33652156

RESUMO

INTRODUCTION: This open-label, phase 1-2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). METHODS: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. RESULTS: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. CONCLUSIONS: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.


Assuntos
Imunoconjugados , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzodiazepinonas , Humanos , Imunoconjugados/uso terapêutico , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico
11.
J Thorac Oncol ; 16(9): 1547-1558, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33607312

RESUMO

INTRODUCTION: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated. METHODS: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS). RESULTS: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports. CONCLUSIONS: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.


Assuntos
Imunoconjugados , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Adulto , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzodiazepinonas , Humanos , Imunoconjugados/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Membrana , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Topotecan/uso terapêutico
12.
J Med Chem ; 64(7): 3697-3706, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33591753

RESUMO

Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (R)-2 (SGC6870). (R)-2 is a potent PRMT6 inhibitor (IC50 = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6-(R)-2 complex and kinetic studies revealed (R)-2 binds a unique, induced allosteric pocket. Additionally, (R)-2 engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, (R)-2's enantiomer, (S)-2 (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, (R)-2 is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.


Assuntos
Benzodiazepinonas/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Regulação Alostérica , Sítio Alostérico , Benzodiazepinonas/síntese química , Benzodiazepinonas/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Proteínas Nucleares/metabolismo , Ligação Proteica , Proteína-Arginina N-Metiltransferases/metabolismo , Estereoisomerismo
13.
Eur J Med Chem ; 213: 113159, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33571911

RESUMO

The family of human muscarinic acetylcholine receptors (MRs) is characterized by a high sequence homology among the five subtypes (M1R-M5R), being the reason for a lack of subtype selective MR ligands. In continuation of our work on dualsteric dibenzodiazepinone-type M2R antagonists, a series of M2R ligands containing a dibenzodiazepinone pharmacophore linked to small basic peptides was synthesized (64 compounds). The linker moiety was varied with respect to length, number of basic nitrogens (0-2) and flexibility. Besides proteinogenic basic amino acids (Lys, Arg), shorter homologues of Lys and Arg, containing three and two methylene groups, respectively, as well as D-configured amino acids were incorporated. The type of linker had a marked impact on M2R affinity and also effected M2R selectivity. In contrast, the structure of the basic peptide rather determined M2R selectivity than M2R affinity. For example, the most M2R selective compound (UR-CG188, 89) with picomolar M2R affinity (pKi 9.60), exhibited a higher M2R selectivity (ratio of Ki M1R/M2R/M3R/M4R/M5R: 110:1:5200:55:2300) compared to the vast majority of reported M2R preferring MR ligands. For selected ligands, M2R antagonism was confirmed in a M2R miniG protein recruitment assay.


Assuntos
Aminoácidos/antagonistas & inibidores , Benzodiazepinonas/farmacologia , Antagonistas Muscarínicos/farmacologia , Peptídeos/farmacologia , Receptor Muscarínico M2/antagonistas & inibidores , Aminoácidos/metabolismo , Animais , Benzodiazepinonas/síntese química , Benzodiazepinonas/química , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/química , Peptídeos/química , Receptor Muscarínico M2/metabolismo , Relação Estrutura-Atividade
14.
Br J Cancer ; 124(5): 893-895, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33257843

RESUMO

Small cell lung cancer (SCLC) is characterised by high relapse rates. Tumour-initiating cells (TICs) are responsible for drug resistance and recurrence of cancer. Rovalpituzumab tesirine (Rova-T), a potent humanised antibody-drug conjugate, selectively targets delta-like protein 3, which is highly expressed in SCLC TICs. The experimental drug CBL0137 (CBL) inhibits the histone chaperone FACT (facilitates chromatin transcription), which is required for the expression of transcription factors that are essential for TIC maintenance. Rova-T and CBL each target SCLC TICs as single agents. However, acquired or intrinsic resistance to single agents is a major problem in cancer. Therefore, we investigated the potential effect of combining Rova-T and CBL in SCLC to eradicate TICs more effectively. Our preclinical studies report a novel and highly translatable therapeutic strategy of dual targeting TICs using Rova-T in combination with CBL to potentially increase survival of SCLC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Apoptose , Benzodiazepinonas/administração & dosagem , Carbazóis/administração & dosagem , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoconjugados/administração & dosagem , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Carcinoma de Pequenas Células do Pulmão/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Talanta ; 222: 121677, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33167283

RESUMO

Non-ribosomal peptides are one class of bacterial metabolites formed by gut microbiota. Intestinal resident Klebsiella oxytoca produces two pyrrolobenzodiazepines, tilivalline and tilimycin, via the same nonribosomal biosynthesis platform. These molecules cause human disease by genotoxic and tubulin inhibitory activities resulting in apoptosis of the intestinal epithelium, loss of barrier integrity and ultimately colitis. Here we report a fast, reliable, HPLC-HR-ESMS2 method for quantifying simultaneously the bacterial enterotoxins tilimycin and tilivalline in complex biological matrices. We synthesized and applied stable isotopically labeled internal standards for precise quantification of the metabolites. Sample preparation was optimized using clinical and laboratory specimens including serum, colonic fluid and stool. The developed method overcame the disadvantage of low selectivity by applying high resolution mass spectrometry in MS2 mode. High sensitivity and low interference from matrices were achieved and validated. We show that the approach is suitable for detection and quantification of the enterotoxic metabolites produced in vivo, in infected human or animal hosts, and in bacterial culture in vitro.


Assuntos
Benzodiazepinonas , Enterotoxinas , Animais , Toxinas Bacterianas , Benzodiazepinas , Cromatografia Líquida de Alta Pressão , Humanos , Pirróis
16.
Int J Mol Sci ; 21(23)2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33260618

RESUMO

Translocator protein (TSPO) and voltage dependent anion channels (VDAC) are two proteins forming a macromolecular complex in the outer mitochondrial membrane that is involved in pleiotropic functions. Specifically, these proteins were described to regulate the clearance of damaged mitochondria by selective mitophagy in non-erythroid immortalized cell lines. Although it is well established that erythroblast maturation in mammals depends on organelle clearance, less is known about mechanisms regulating this clearance throughout terminal erythropoiesis. Here, we studied the effect of TSPO1 downregulation and the action of Ro5-4864, a drug ligand known to bind to the TSPO/VDAC complex interface, in ex vivo human terminal erythropoiesis. We found that both treatments delay mitochondrial clearance, a process associated with reduced levels of the PINK1 protein, which is a key protein triggering canonical mitophagy. We also observed that TSPO1 downregulation blocks erythroblast maturation at the orthochromatic stage, decreases the enucleation rate, and increases cell death. Interestingly, TSPO1 downregulation does not modify reactive oxygen species (ROS) production nor intracellular adenosine triphosphate (ATP) levels. Ro5-4864 treatment recapitulates these phenotypes, strongly suggesting an active role of the TSPO/VDAC complex in selective mitophagy throughout human erythropoiesis. The present study links the function of the TSPO/VDAC complex to the PINK1/Parkin-dependent mitophagy induction during terminal erythropoiesis, leading to the proper completion of erythroid maturation.


Assuntos
Núcleo Celular/metabolismo , Regulação para Baixo , Eritropoese , Mitocôndrias/metabolismo , Mitofagia , Receptores de GABA/metabolismo , Benzodiazepinonas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Humanos , Cinética , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Fenótipo , RNA Interferente Pequeno/metabolismo
17.
Bioorg Med Chem Lett ; 30(19): 127456, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739400

RESUMO

The protein kinase TNK2 (ACK1) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role transmitting cell survival, growth and proliferative signals via modification of multiple downstream effectors by unique tyrosine phosphorylation events. Scaffold morphing based on our previous TNK2 inhibitor XMD8-87 identified urea 17 from which we developed the potent and selective compound 32. A co-crystal structure was obtained showing 32 interacting primarily with the main chain atoms of an alanine residue of the hinge region. Additional H-bonds exist between the urea NHs and the Thr205 and Asp270 residues.


Assuntos
Benzodiazepinonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Benzodiazepinonas/síntese química , Benzodiazepinonas/metabolismo , Linhagem Celular , Cristalografia por Raios X , Estabilidade de Medicamentos , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Relação Estrutura-Atividade
18.
Rev. neurol. (Ed. impr.) ; 71(4): 143-150, 16 ago., 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-195462

RESUMO

INTRODUCCIÓN: Numerosos fármacos se han relacionado con el agravamiento de síntomas en pacientes con miastenia grave, pero hasta la fecha no existen estudios sobre la exposición a fármacos en estos pacientes. OBJETIVOS: Describir el consumo de fármacos y calcular la tasa anual de episodios de exacerbación en una cohorte de pacientes con miastenia grave, y explorar posibles factores de riesgo de exacerbaciones graves. PACIENTES Y MÉTODOS: Estudio observacional longitudinal retrospectivo que incluye a pacientes adultos con miastenia grave seguidos en consulta. Cálculo de frecuencias, tasas y construcción de modelo de eventos repetidos. RESULTADOS: De 91 pacientes incluidos, el 94,51% estuvo expuesto al menos a un fármaco durante el período de estudio (siete años y un mes). De ellos, 51 tuvieron al menos una prescripción de un fármaco contraindicado en la ficha técnica (56,04%). Se contabilizaron 145 exacerbaciones en 50 pacientes. La tasa anual de incidencia fue de 0,35 exacerbaciones por paciente y año. De estas exacerbaciones, 48 fueron graves (en 18 pacientes), con una tasa anual de incidencia de 0,12. Se halló una posible asociación entre diagnóstico de miastenia grave generalizada y timectomía, con un aumento del riesgo de episodios de exacerbación graves. CONCLUSIONES: En esta cohorte se encontró una amplia exposición a fármacos, pero no asociación con el riesgo de episodios de exacerbación graves. Algo más de la mitad de pacientes tuvo al menos un episodio de exacerbación durante el período de estudio, la mayoría leves. Son necesarios estudios que corroboren estas conclusiones y puedan estudiar posibles correlaciones entre fármacos y el riesgo de episodios de exacerbación


INTRODUCTION: Numerous drugs have been related to exacerbation of myasthenia gravis. So far there are no studies examining the extent of use of drugs related to exacerbation of myasthenia gravis. AIMS: We sought to assess the extent of use of drugs related to exacerbations and the annual incidence rate of exacerbations in a cohort of myasthenia gravis patients. We explored possible risk factors of severe exacerbations. PATIENTS AND METHODS: We performed a retrospective cohort study. We included adult patients followed in neurology department. We estimated frequencies, rates and built a recurrent events model. RESULTS: We included 91 patients. 94.51% of patients had at least one prescription of a drug. 51 patients had at least one prescription of a drug contraindicated according to its drug label. 145 exacerbation episodes were reported in 50 patients. The annual incidence rate of exacerbation episodes was 0.35. 48 exacerbations were severe (in 18 patients). The annual incidence rate of severe exacerbation episodes was 0.12. Generalized myasthenia gravis and thymectomy were associated with a higher risk of severe exacerbation episodes. CONCLUSIONS: Our patients were extensive and widespread exposed to drugs during the follow-up period but we did not find and association with severe exacerbation episodes. Just over half of the patients had at least one exacerbation episode during the study period, most of them were mild. Further studies with larger sample sizes are necessary to corroborate these conclusions and to study possible correlations between the use of drugs and the risk of exacerbation episodes


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Miastenia Gravis/induzido quimicamente , Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Miastenia Gravis/fisiopatologia , Fatores de Risco , Estudos Longitudinais , Estudos Retrospectivos , Timectomia/estatística & dados numéricos , Intervalos de Confiança , Benzodiazepinonas/efeitos adversos
19.
ChemMedChem ; 15(18): 1752-1756, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32686307

RESUMO

DNA-encoded chemical libraries (DECLs) are collections of chemical moieties individually coupled to distinctive DNA barcodes. Compounds can be displayed either at the end of a single DNA strand (i. e., single-pharmacophore libraries) or at the extremities of two complementary DNA strands (i. e., dual-pharmacophore libraries). In this work, we describe the use of a dual-pharmacophore encoded self-assembly chemical (ESAC) library for the affinity maturation of a known 4,5-dihydrobenzodiazepinone ring (THBD) acetyl-lysine (KAc) mimic for the cyclic-AMP response element binding protein (CREB) binding protein (CREBBP or CBP) bromodomain. The new pair of fragments discovered from library selection showed a sub-micromolar affinity for the CREBBP bromodomain in fluorescence polarization and ELISA assays, and selectivity against BRD4(1).


Assuntos
Benzodiazepinonas/farmacologia , Proteína de Ligação a CREB/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Benzodiazepinonas/síntese química , Benzodiazepinonas/química , Proteína de Ligação a CREB/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Modelos Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Fatores de Transcrição/metabolismo
20.
J Med Chem ; 63(15): 8114-8133, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32648758

RESUMO

High-throughput screening has shown that Retro-1 inhibits ricin and Shiga toxins by diminishing their intracellular trafficking via the retrograde route, from early endosomes to the Golgi apparatus. To improve the activity of Retro-1, a structure-activity relationship (SAR) study was undertaken and yielded an analogue with a roughly 70-fold better half-maximal effective concentration (EC50) against Shiga toxin cytotoxicity measured in a cell protein synthesis assay.


Assuntos
Benzodiazepinonas/química , Benzodiazepinonas/farmacologia , Toxinas Shiga/antagonistas & inibidores , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Células HeLa , Humanos , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Toxinas Shiga/metabolismo , Relação Estrutura-Atividade
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