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1.
ACS Chem Neurosci ; 13(9): 1395-1409, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35442021

RESUMO

Synthetic cannabinoid receptor agonists (SCRAs) are a large and growing class of new psychoactive substances (NPSs). Two recently identified compounds, MEPIRAPIM and 5F-BEPIRAPIM (NNL-2), have not been confirmed as agonists of either cannabinoid receptor subtype but share structural similarities with both SCRAs and a class of T-type calcium channel (CaV3) inhibitors under development as new treatments for epilepsy and pain. In this study, MEPIRAPIM and 5F-BEPIRAPIM and 10 systematic analogues were synthesized, analytically characterized, and pharmacologically evaluated using in vitro cannabinoid receptor and CaV3 assays. Several compounds showed micromolar affinities for CB1 and/or CB2, with several functioning as low potency agonists of CB1 and CB2 in a membrane potential assay. 5F-BEPIRAPIM and four other derivatives were identified as potential CaV3 inhibitors through a functional calcium flux assay (>70% inhibition), which was further confirmed using whole-cell patch-clamp electrophysiology. Additionally, MEPIRAPIM and 5F-BEPIRAPIM were evaluated in vivo using a cannabimimetic mouse model. Despite detections of MEPIRAPIM and 5F-BEPIRAPIM in the NPS market, only the highest MEPIRAPIM dose (30 mg/kg) elicited a mild hypothermic response in mice, with no hypothermia observed for 5F-BEPIRAPIM, suggesting minimal central CB1 receptor activity.


Assuntos
Canais de Cálcio Tipo T , Canabinoides , Hipotermia , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/química , Canabinoides/farmacologia , Indazóis/farmacologia , Camundongos , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Receptores de Canabinoides
2.
ACS Chem Neurosci ; 13(8): 1281-1295, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35404067

RESUMO

Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS). They commonly comprise N-alkylated indole, indazole, or 7-azaindole scaffolds with amide-linked pendant amino acid groups. To explore the contribution of the amino acid side chain to the cannabinoid pharmacology of SCRA NPS, a systematic library of side chain-modified SCRAs was prepared based on the recent detections of amino acid derivatives 17 (5F-AB-PINACA), 18 (5F-ADB-PINACA), 15 (PX-1), 19 (PX-2), and 20 (NNL-1). In vitro binding affinities and functional activities at cannabinoid type 1 and 2 receptors (CB1 and CB2, respectively) were determined for all the library members using radioligand competition experiments and a fluorescence-based membrane potential assay. Binding affinities and functional activities varied widely across compounds (Ki = 0.32 to >10 000 nM, EC50 = 0.24-1259 nM), with several clear structure-activity relationships (SARs) emerging. Affinity and potency at CB1 changed as a function of the heterocyclic core (indazole > indole > 7-azaindole) and the pendant amino acid side chain (tert-butyl > iso-propyl > iso-butyl > benzyl > ethyl > methyl > hydrogen). Ensemble docking at CB1 revealed a clear steric basis for observed SAR trends. Interestingly, although 15 (PX-1) and 19 (PX-2) have been detected in recreational drug markets, they failed to induce centrally CB1-mediated effects (e.g., hypothermia) in mice using radiobiotelemetry. Together, these data provide insights regarding structural contributions to the cannabimimetic profiles of 17 (5F-AB-PINACA), 18 (5F-ADB-PINACA), 15 (PX-1), 19 (PX-2), 20 (NNL-1), and other SCRA NPS.


Assuntos
Agonistas de Receptores de Canabinoides , Canabinoides , Animais , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/química , Fármacos do Sistema Nervoso Central , Indazóis/química , Indazóis/farmacologia , Camundongos , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Receptores de Canabinoides , Valina/análogos & derivados
3.
Bioengineered ; 13(4): 10944-10955, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35477364

RESUMO

Breast cancer is characterized by high morbidity and mortality. GDC-0941 is a PI3K inhibitor with oncogenic effects in breast cancer. However, certain breast cancer cells are insensitive to GDC-0941. Hence, the mechanism of GDC-0941 in breast cancer resistance was investigated in this study. Breast cancer cell lines BT-474, MCF7, Hs-578-T, MDA-MB-231, MDA-MB-453, and MDA-MB-468 were cultured in different medium and then treated with 100 or 500 nM GDC-0941, 100 nM OSU-T315, or TNF-α antibody. Moreover, ILK and shILK were transfected into cells. The half maximal inhibitory concentrations (IC50) for GDC-0941 were detected using CCK-8 assay. The levels of ILK, AKT, PDK1, S6, and p70S6K expression were detected using western blotting and qPCR. In addition, the mouse model of breast cancer was constructed to measure the tumor size, volume, and weight. The results showed that GDC-0941 decreased cell survival rate, downregulated the phosphorylation of AKT, S6, and p70S6K, and promoted the expression of ILK, while it had little effect on PDK1 expression. GDC-0941 inhibited the increases in p-AKT, p-S6, and p-p70S6K caused by ILK overexpression and promoted ILK knockdown-induced reduction of p-AKT, p-S6, and p-p70S6K. In addition, the combination of OSU-T315 and GDC-0941 decreased p-AKT, p-S6, and p-p70S6K level, tumor volume, and tumor weight. GDC-0941 promoted ILK expression by upregulating TNF-α level. Taken together, GDC-0941 increased ILK level by upregulating TNF-α, thus affecting AKT expression and the sensitivity of breast cancer cells to GDC-0941.


Assuntos
Neoplasias da Mama , Proteínas Quinases S6 Ribossômicas 70-kDa , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Indazóis , Integrinas , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sulfonamidas , Fator de Necrose Tumoral alfa/genética
4.
J Immunother Cancer ; 10(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35459733

RESUMO

During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the-possibly altered-response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.


Assuntos
COVID-19 , Inibidores de Janus Quinases , Antivirais/uso terapêutico , Azetidinas , COVID-19/tratamento farmacológico , Citocinas/metabolismo , Humanos , Imidazóis , Indazóis , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Piperidinas , SARS-CoV-2
5.
Bioorg Chem ; 122: 105735, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35298962

RESUMO

Tremendous research is focused on developing novel drug candidates targeting microtubules to inhibit their function in several cellular processes, including cell division. In this regard, several indazole derivatives were sought to target the colchicine binding site on the ß-tubulin, a crucial protein required to form microtubules, to develop microtubule targeting agents. Even though there are several reviews on the indazole-based compounds, none of them focused on using indazole scaffold to develop microtubule targeting agents. Therefore, this review aims to present the advances in research on compounds containing indazole scaffolds as microtubule targeting agents based on the articles published in the last two decades. Among the articles reviewed, we found that compounds 6 and 7 showed the lowest IC50 values of 0.6 âˆ¼ 0.9 nM in the cell line studies, making them the strongest indazole derivatives that target microtubules. The compounds 30, 31, 37 (IC50 = ∼ 1 nM) and compounds 8, 38 (IC50 = ∼ 2 nM) have proved to be potent microtubule inhibitors. The compounds 18, 31, 44, 45 also showed strong anticancer activity (IC50 = ∼ 8 nM). It is important to notice that except for compounds 9, 12, 13, 15, and SRF, the top activity compounds including 6, 7, 8, 10, 11, 30, 31, 37, 44, and 45 contain 3,4,5­trimethoxyphenyl substitution similar to that of colchicine. Therefore, it appears that the 3,4,5­trimethoxyphenyl substituent on the indazole scaffold is crucial for targeting CBS.


Assuntos
Antineoplásicos , Indazóis , Antineoplásicos/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Colchicina/metabolismo , Colchicina/farmacologia , Indazóis/metabolismo , Indazóis/farmacologia , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química
6.
J Med Chem ; 65(7): 5724-5750, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35357160

RESUMO

Endocrine therapies in the treatment of early and metastatic estrogen receptor α positive (ERα+) breast cancer (BC) are greatly limited by de novo and acquired resistance. Selective estrogen receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization of LSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno[2,3-e]indazole. Subsequent acrylic acid degron modifications led us to identify compound 40 as the preferred candidate. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently, 40 is being evaluated in preclinical trials.


Assuntos
Antineoplásicos , Neoplasias da Mama , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , Células MCF-7 , Camundongos , Receptores de Estrogênio/metabolismo , Tiofenos
7.
Bioorg Med Chem Lett ; 64: 128654, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35259487

RESUMO

In this study, a novel batch of indazole containing 1,2,3-triazole agents were designed and synthesized. The antiproliferative activity of target compounds in four human cancer cells, PC-3 (human prostate cancer cell), MCF-7 (human breast cancer cell), HepG-2 (human hepatoma cell) and MGC-803 (human gastric cancer cell), was evaluated by thiazole blue (MTT). In the antiproliferative activity screening, we were surprised to find that most compounds have specific cytotoxicity to PC-3 cancer cells. In particular, 9a has an IC50 value of 4.42 ± 0.06 µmol/L against PC-3 cell. Cloning experiments showed that 9a could inhibit the formation of PC-3 cancer cell clone in a dose-dependent manner. Through cell cycle arrest experiment, we found that compound 9a can block the cell cycle in G2/M phase and inhibit cell proliferation. Finally, by evaluating the safety of compound 9a, we noticed that it showed fairly good safety both in vivo and in vitro. Overall, based on the biological activity evaluation and safety, analogue 9a can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.


Assuntos
Antineoplásicos , Neoplasias da Próstata , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/farmacologia , Masculino , Estrutura Molecular , Neoplasias da Próstata/tratamento farmacológico , Esqueleto , Relação Estrutura-Atividade , Triazóis/farmacologia
8.
Future Oncol ; 18(17): 2063-2074, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35232230

RESUMO

Aims: To compare clinical trial results for crizotinib and entrectinib in ROS1-positive non-small-cell lung cancer and compare clinical trial data and real-world outcomes for crizotinib. Patients & methods: We analyzed four phase I-II studies using a simulated treatment comparison (STC). A STC of clinical trial versus real-world evidence compared crizotinib clinical data to real-world outcomes. Results: Adjusted STC found nonsignificant trends favoring crizotinib over entrectinib: objective response rate, risk ratio = 1.04 (95% CI: 0.85-1.28); median duration of response, mean difference = 16.11 months (95% CI: -1.57- 33.69); median progression-free survival, mean difference = 3.99 months (95% CI: -6.27-14.25); 12-month overall survival, risk ratio = 1.01 (95% CI: 0.90-1.12). Nonsignificant differences were observed between the trial end point values and the real-world evidence for crizotinib. Conclusions: Crizotinib and entrectinib have comparable efficacy in ROS1-positive non-small-cell lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Benzamidas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos como Assunto , Crizotinibe/uso terapêutico , Humanos , Indazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Resultado do Tratamento
9.
Eur J Med Chem ; 235: 114281, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35344903

RESUMO

To synergistically treat glioma with a combination chemotherapy, we design and prepare novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties, which could intelligently deliver redox-sensitive doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND). The pH-responsive ligand Chol-TPG modified by PEGylated glucose can overcome the blood-brain barrier and reach tumor cells. Combined with the modification of mitochondria targeting ligand (Chol-TPP), Lip-TPGS are endowed with pH-responsive charge regulation function and multi-stage targeting abilities. After triggered by the excessive glutathione in tumor cells, Lip-TPGS could sufficiently release the parent drugs DOX, which would significantly reduce side effects without compromising anti-glioma efficacy. Therefore, Lip-TPGS possess these characteristics: good pharmacokinetic behavior, superior brain targeting ability, specific tumor recognition and internalization capability, and strong endo/lysosome escaping and mitochondria targeting potential. Furthermore, Lip-TPGS exhibit significant advantages on anti-glioma by inhibiting proliferation, promoting apoptosis, inducing mitochondria dysfunction, inhibiting migration and invasion, prolonging the survival time, narrowing tumor areas, limiting lung metastasis, and reducing toxicity to normal organs. In summary, Lip-TPGS, with cascade targeting abilities from tissue/cell to organelle levels and highly controlled drug release properties, would become a promising drug delivery system for glioma treatment.


Assuntos
Glioma , Pró-Fármacos , Linhagem Celular Tumoral , Doxorrubicina , Glioma/tratamento farmacológico , Glucose , Humanos , Concentração de Íons de Hidrogênio , Indazóis , Ligantes , Lipossomos/uso terapêutico , Oxirredução , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico
10.
Leg Med (Tokyo) ; 56: 102053, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35279624

RESUMO

The objective of the present study was the development and validation of the method for determining AMB-FUBINACA and its metabolite - AMB-FUBINACA O-desmethyl acid - in blood samples, followed by verification of the method in toxicological judicial and forensic medicine practice employing the example of post-aggression suicide. Most likely in consequence of development of adverse effects resulting in psychotic symptoms, a male being under the influence of the synthetic cannabinoid AMB-FUBINACA and the new synthetic opioid U-47700, mortally wounded his female partner and subsequently committed suicide. Identification and determination of the afore-mentioned xenobiotics in blood samples collected from the male and female victims were performed employing high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The analytes were isolated from blood samples using the solid phase extraction (SPE) method. The blood samples collected from the male and female demonstrated respectively 110 and 196 ng/mL of AMB-FUBINACA O-desmethyl acid metabolite, 1935 and 357 ng/mL of U-47700, 250 and 200 ng/mL of N-desmethyl-U-47700, as well as 410 and 200 ng/mL of N,N-didesmethyl-U-47700. The concentration values of new psychoactive substances (NPS's) in blood samples originating from the male and female were within the ranges encountered in cases of poisoning, including these resulting in death. Nevertheless, the evident signs of exsanguination proof that the woman was alive when she sustained lethal injuries. The presented cases illustrate the difficult to be anticipated effect exerted on the users by NPS's.


Assuntos
Suicídio , Espectrometria de Massas em Tandem , Agressão , Benzamidas , Feminino , Humanos , Indazóis , Masculino , Espectrometria de Massas em Tandem/métodos , Valina/análogos & derivados
11.
Chem Commun (Camb) ; 58(28): 4435-4455, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35294515

RESUMO

Indazole and pyrazole are renowned as a prodigious class of heterocycles having versatile uses in medicinal as well as industrial chemistry. Considering sustainable approaches, recently, photocatalysis has become an indispensable tool in organic chemistry due to its application for the activation of small molecules and the use of a clean energy source. In this review, we have highlighted the use of metal-based photocatalysts, organic photoredox catalysts, energy transfer photocatalysts and electron-donor-acceptor complexes in the functionalization of indazole and pyrazole. This perspective is arranged based on the types of functionalization reactions on indazole and pyrazole. A detailed discussion regarding the reaction mechanism of each reaction is given to provide a comprehensive guide to the reader. Finally, a summary of existing challenges and the future outlook towards the development of efficient photocatalytic methods for functionalization of these heterocycles is also presented.


Assuntos
Indazóis , Luz , Catálise , Pirazóis
12.
Inorg Chem ; 61(12): 4919-4937, 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35285628

RESUMO

Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.


Assuntos
Antineoplásicos , Complexos de Coordenação , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Cristalografia por Raios X , Humanos , Indazóis , Ligantes , Estrutura Molecular
13.
J Immunother Cancer ; 10(3)2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35332062

RESUMO

BACKGROUND: Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin-paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer. METHODS: IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin-paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination. RESULTS: A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin-paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin-paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A-D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A-D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A-D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%. CONCLUSIONS: Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens. TRIAL REGISTRATION NUMBER: NCT03307785.


Assuntos
Antineoplásicos , Neoplasias , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Carboplatina , Humanos , Indazóis , Neoplasias/patologia , Paclitaxel , Piperidinas , Fator A de Crescimento do Endotélio Vascular
14.
Clin Lab ; 68(2)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35142203

RESUMO

BACKGROUND: The goal of this study was to evaluate the predictive and prognostic importance of the lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (DNLR), and systemic immune inflammation index (SSI) in STS cases treated with pazopanib. METHODS: Thirty STS patients treated with pazopanib were included in this study. SSI, DNLR, LMR, and NLR values were calculated at baseline and in the first month. Median values of these predictors in these patients (SSI (944), DNLR (1.8), LMR (2.7), and NLR (3.0)) were taken as cutoff values. The associations between the survival time (both overall survival (OS) and progression-free survival (PFS)) and cutoff values were evaluated using Kaplan Meier curves and Cox regression models. RESULTS: Patients with low SSI, NLR, and DNLR values at pretreatment and after the initial response had longer OS (for OS - p = 0.024, p = 0.015, and p = 0.041, respectively). Longer OS was also found in patients who showed increasing LMR and decreasing NLR after one month of therapy (for ΔLMR, p = 0.016; for ΔNLR, p = 0.016). Pa-tients with low SSI and NLR values at pretreatment and after the initial response had longer PFS (for PFS, p = 0.014, p = 0.04, p ˂ 0.001, respectively). In terms of initial responses to treatment, SSI, NLR, DNLR, and increased LMR were detected as independent risk factors in univariate analysis, but initial response was found to be the only independent risk factor for PFS in multivariate analysis. CONCLUSIONS: Low values of SSI, NLR, and DNLR at pretreatment and at initial response may predict long-term survival rates. After one month of treatment with pazopanib, decreased NLR and increased LMR are predictive of favorable outcomes in these cases.


Assuntos
Sarcoma , Sulfonamidas , Humanos , Indazóis , Linfócitos , Neutrófilos , Prognóstico , Pirimidinas/efeitos adversos , Estudos Retrospectivos , Sarcoma/tratamento farmacológico , Sulfonamidas/uso terapêutico
15.
Clin Cancer Res ; 28(7): 1302-1312, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35144967

RESUMO

PURPOSE: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. PATIENTS AND METHODS: Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. RESULTS: At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0-38.2]; median PFS was 13.8 months (95% CI, 10.1-19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8-89.1) and median intracranial DoR was 22.1 (95% CI, 7.4-not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. CONCLUSIONS: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Benzamidas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Criança , Humanos , Indazóis , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas
16.
Brain Res Bull ; 182: 80-89, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35182690

RESUMO

Inflammatory responses in the brain play an etiological role in the development of epilepsy, suggesting that finding novel molecules for controlling neuroinflammation may have clinical value in developing the disease-modifying strategies for epileptogenesis. Adjudin, a multi-functional small molecule compound, has pleiotropic effects, including anti-inflammatory properties. In the present study, we aimed to investigate the effects of adjudin on pilocarpine-induced status epilepticus (SE) and its role in the regulation of reactive gliosis and neuroinflammation. SE was induced in male C57BL/6 mice that were then treated with adjudin (50 mg/kg) for 3 days after SE onset. Immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and western blot analysis were used to evaluate the effects of adjudin treatment in the hippocampus after SE. Our results showed that adjudin treatment significantly mitigated apoptotic cell death in the hippocampus after SE onset. Moreover, adjudin treatment suppressed SE-induced glial activation and activation of mammalian target of rapamycin signaling in the hippocampus. Concomitantly, adjudin treatment significantly reduced SE-induced inflammatory processes, as confirmed by changes in the expression of inflammatory mediators such as tumor necrosis factor-α, interleukin-1ß, and arginase-1. In conclusion, these findings suggest that adjudin may serve as a potential neuroprotective agent for preventing pathological mechanisms implicated in epileptogenesis.


Assuntos
Pilocarpina , Estado Epiléptico , Animais , Hidrazinas , Indazóis , Masculino , Mamíferos , Camundongos , Camundongos Endogâmicos C57BL , Pilocarpina/toxicidade , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Serina-Treonina Quinases TOR
17.
J Med Chem ; 65(5): 3849-3865, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35191698

RESUMO

PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable. Through the scaffold-hopping strategy, indazole was first described as the core structure of propeller-shaped PI3Kδ inhibitors. A total of 26 indazole derivatives were designed and prepared to identify a novel compound 9x with good isoform selectivity, PK profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic (PD) studies showed that 9x exhibits superior efficacy in HCC cell lines and xenograft models, and the mechanistic study showed that 9x robustly suppresses the downstream AKT pathway to induce subsequent apoptotic cell death in HCC models. Therefore, this work provides a new structural design of PI3Kδ inhibitors for a novel and efficient therapeutic small molecule toward HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
18.
Toxicol Sci ; 187(1): 175-185, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35201352

RESUMO

Synthetic cannabinoid receptor agonists (SCRAs) are a large group of abused psychoactive compounds that elicit numerous toxic effects not observed with cannabis, including death. Abuse of third-generation SCRA 5F-MDMB-PINACA (also known as 5F-ADB) has been associated with over 40 fatalities. This SCRA is metabolized to several active phase I metabolites, including excessively high post-mortem serum concentrations of an ester hydrolysis metabolite, 5F-MDMB-PINACA-M7 (M7). Although high serum concentrations of M7 (and other active metabolites) have been suggested to contribute to 5F-MDMB-PINACA toxicity, the affinity of M7 for CB1 receptors is unknown and more complete pharmacodynamic characterization of 5F-MDMB-PINACA and its active metabolites is needed. Competition binding and G-protein modulation studies presented here confirm reports that 5F-MDMB-PINACA and a second N-5-hydroxypentyl metabolite (M2) exhibit nM affinity and act as high efficacy agonists at CB1 receptors. Also as previously published, M7 exhibits high efficacy at CB1 receptors; however, demonstrated here for the first time, M7 retains only low µΜ affinity. Empirically derived Kb values indicate rimonabant differentially antagonizes G-protein activation produced by 5F-MDMB-PINACA, relative to Δ9-THC (THC) or its metabolites. Chronic administration of 5F-MDMB-PINACA and metabolites results in CB1 down-regulation, but only 5F-MDMB-PINACA produces desensitization. Although low CB1 affinity/potency of M7 precluded in vivo studies, both M2 and THC produce locomotor suppression and CB1-mediated dose-dependent hypothermia and analgesia in mice. Collectively, these data confirm and extend previous studies suggesting that 5F-MDMB-PINACA is metabolized to active compounds exhibiting atypical pharmacodynamic properties at CB1 receptors, that may accumulate with parent drug to produce severe toxicity.


Assuntos
Canabinoides , Receptor CB1 de Canabinoide , Animais , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/toxicidade , Canabinoides/toxicidade , Dronabinol/toxicidade , Indazóis , Camundongos
19.
Int J Mol Sci ; 23(3)2022 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-35163171

RESUMO

Excessive glucose metabolism and disruptions in Wnt signaling are important molecular changes present in oral cancer cells. The aim of this study was to evaluate the effects of the combinatorial use of glycolysis and Wnt signaling inhibitors on viability, cytotoxicity, apoptosis induction, cell cycle distribution and the glycolytic activity of tongue carcinoma cells. CAL 27, SCC-25 and BICR 22 tongue cancer cell lines were used. Cells were treated with inhibitors of glycolysis (2-deoxyglucose and lonidamine) and of Wnt signaling (PRI-724 and IWP-O1). The effects of the compounds on cell viability and cytotoxicity were evaluated with MTS and CellTox Green tests, respectively. Apoptosis was evaluated by MitoPotential Dye staining and cell cycle distribution by staining with propidium iodide, followed by flow cytometric cell analysis. Glucose and lactate concentrations in a culture medium were evaluated luminometrically. Combinations of 2-deoxyglucose and lonidamine with Wnt pathway inhibitors were similarly effective in the impairment of oral cancer cells' survival. However, the inhibition of the canonical Wnt pathway by PRI-724 was more beneficial, based on the glycolytic activity of the cells. The results point to the therapeutic potential of the combination of low concentrations of glycolytic modulators with Wnt pathway inhibitors in oral cancer cells.


Assuntos
Neoplasias da Língua/metabolismo , Via de Sinalização Wnt/fisiologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose/farmacologia , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Indazóis/farmacologia , Pirimidinonas/farmacologia , Língua/metabolismo , Língua/patologia , Neoplasias da Língua/tratamento farmacológico , Via de Sinalização Wnt/genética
20.
Cancer Chemother Pharmacol ; 89(3): 363-372, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35118559

RESUMO

PURPOSE: Entrectinib is an anti-cancer agent that inhibits TRKA/B/C, ROS1, and ALK. Secondary pharmacokinetic (PK) exposure parameters for entrectinib derived from a previously described population PK model were used to characterize exposure-response relationships in patients treated with entrectinib. METHODS: Data were pooled from Phase 1 and 2 studies of entrectinib (600-800 mg/day in adults, 250-750 mg/m2/day in children) in 293 patients with NTRK-, ROS1-, or ALK-positive, locally advanced or metastatic tumors. Efficacy was evaluated by the changes in sum of target lesion diameters and best overall response defined by RECIST1.1. A longitudinal nonlinear mixed-effect model described the relationship between entrectinib exposure and tumor size data in patients with ROS1-positive non-small-cell lung cancer (NSCLC) or NTRK fusion-positive solid tumors. The relationship between exposure and treatment-emergent (TEAEs) or serious (SAEs) adverse events was assessed by logistic regression in all patients for whom secondary PK parameter estimates were derived. RESULTS: Among the 89 patients with evaluable efficacy data included in the exposure-efficacy analysis, 73% (65/89) achieved a complete or partial response. Entrectinib exposure distribution was similar in responders and non-responders. Model-described tumor shrinkage rates were 8-12 times greater than growth rates in both ROS-1-positive NSCLC patients and NTRK fusion-positive solid tumor patients, with no relationship between exposure and these rates. The probability of experiencing a Grade ≥ 3 TEAE or SAE increased with exposure, primarily at doses > 600 mg/day. CONCLUSION: These analyses supported that entrectinib at 600 mg/day provides an acceptable benefit-risk ratio in adults with NTRK-, ROS1-, or ALK-positive tumors, considered as rare disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Segunda Neoplasia Primária , Adulto , Benzamidas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Criança , Humanos , Indazóis , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases
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