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1.
Cells ; 10(12)2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34944068

RESUMO

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving EGFR-D770 to EGFR-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. EGFR-D770>GY and other EGFR insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of EGFR exon 20 insertion mutated lung cancer (n = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and dacomitinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with EGFR-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.


Assuntos
Afatinib/farmacologia , Receptores ErbB/genética , Éxons/genética , Mutagênese Insercional/genética , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Sequência de Aminoácidos , Animais , Linhagem Celular , Modelos Animais de Doenças , Receptores ErbB/química , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Estadiamento de Neoplasias
2.
J Enzyme Inhib Med Chem ; 36(1): 2055-2067, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34551654

RESUMO

A series of quinazolin-4(3H)-one derivatives were synthesised and evaluated for their cytotoxicity against human Caucasian breast adenocarcinoma (MCF-7) and human ovarian carcinoma (A2780) cell lines. Cytotoxicity of the most tested compounds was 2- to 30-fold more than the positive control lapatinib (IC50 of 2j = 3.79 ± 0.96; 3j = 0.20 ± 0.02; and lapatinib = 5.9 ± 0.74) against MCF7 cell lines except two compounds (IC50 of 2 b = 15.72 ± 0.07 and 2e = 14.88 ± 0.99). On the other hand, cytotoxicity was 4 - 87 folds (IC50 of 3a = 3.00 ± 1.20; 3 g = 0.14 ± 0.03) more the positive control lapatinib (IC50 = 12.11 ± 1.03) against A2780 cell lines except compound 2e (IC50 = 16.43 ± 1.80). Among the synthesised quinazolin-4(3H)-one derivatives, potent cytotoxic 2f-j and 3f-j were investigated for molecular mechanism of action. Inhibitory activities of the compounds were tested against multiple tyrosine protein kinases (CDK2, HER2, EGFR and VEGFR2) enzymes. As expected, all the quinazolin-4(3H)-one derivatives were showed comparable inhibitory activity against those kinases tested, especially, compound 2i and 3i showed potent inhibitory activity against CDK2, HER2, EGFR tyrosine kinases. Therefore, molecular docking analysis for quinazolin-4(3H)-one derivatives 2i and 3i were performed, and it was revealed that compounds 2i and 3i act as ATP non-competitive type-II inhibitor against CDK2 kinase enzymes and ATP competitive type-I inhibitor against EGFR kinase enzymes. However, in case of HER2, compounds 2i act as ATP non-competitive type-II inhibitor and 3i act as ATP competitive type-I inhibitor. Docking results of known inhibitors were compared with synthesised compounds and found synthesised 2i and 3i are superior than the known inhibitors in case of interactions. In addition, in silico drug likeness properties of quinazolin-4(3H)-one derivatives showed better predicted ADME values than lapatinib.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
3.
PLoS One ; 16(9): e0257206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34506566

RESUMO

Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.


Assuntos
Imidazóis/farmacologia , Indóis/farmacologia , Oximas/farmacologia , Purinas/farmacologia , Quinazolinonas/farmacologia , Sequência de Aminoácidos , Antivirais/química , Antivirais/farmacologia , Imidazóis/química , Indóis/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Oximas/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Estrutura Secundária de Proteína , Purinas/química , Quinazolinonas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química
4.
Genes (Basel) ; 12(6)2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208492

RESUMO

Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. Here, using a medicinal chemistry approach, we aimed to improve the potency of B02. We identified the B02 analog, B02-isomer, which inhibits HR in human cells with significantly higher efficiency. We also show that B02-iso sensitizes triple-negative breast cancer MDA-MB-231 cells to the PARP inhibitor (PARPi) olaparib.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Recombinação Homóloga/efeitos dos fármacos , Quinazolinonas/farmacologia , Rad51 Recombinase/antagonistas & inibidores , Antineoplásicos/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Ftalazinas/farmacologia , Piperazinas/farmacologia , Ligação Proteica , Quinazolinonas/química , Rad51 Recombinase/química , Rad51 Recombinase/metabolismo
5.
PLoS One ; 16(7): e0254794, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34310628

RESUMO

Iron and other transition metals, such as copper and manganese, are essential for supporting brain function, yet over-accumulation is cytotoxic. This over-accumulation of metals, particularly iron, is common to several neurological disorders; these include Alzheimer's disease, Parkinson's disease, Friedrich's ataxia and other disorders presenting with neurodegeneration and associated brain iron accumulation. The management of iron flux by the blood-brain barrier provides the first line of defense against the over-accumulation of iron in normal physiology and in these pathological conditions. In this study, we determined that the iron chelator PBT434, which is currently being developed for treatment of Parkinson's disease and multiple system atrophy, modulates the uptake of iron by human brain microvascular endothelial cells (hBMVEC) by chelation of extracellular Fe2+. Treatment of hBMVEC with PBT434 results in an increase in the abundance of the transcripts for transferrin receptor (TfR) and ceruloplasmin (Cp). Western blot and ELISA analyses reveal a corresponding increase in the proteins as well. Within the cell, PBT434 increases the detectable level of chelatable, labile Fe2+; data indicate that this Fe2+ is released from ferritin. In addition, PBT434 potentiates iron efflux likely due to the increase in cytosolic ferrous iron, the substrate for the iron exporter, ferroportin. PBT434 equilibrates rapidly and bi-directionally across an hBMVEC blood-brain barrier. These results indicate that the PBT434-iron complex is not substrate for hBMVEC uptake and thus support a model in which PBT434 would chelate interstitial iron and inhibit re-uptake of iron by endothelial cells of the blood-brain barrier, as well as inhibit its uptake by the other cells of the neurovascular unit. Overall, this presents a novel and promising mechanism for therapeutic iron chelation.


Assuntos
Encéfalo/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Ferro/efeitos adversos , Quinazolinonas/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Antígenos CD/genética , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ceruloplasmina/genética , Células Endoteliais/efeitos dos fármacos , Ferritinas/genética , Humanos , Ferro/metabolismo , Proteínas de Membrana/genética , Microcirculação/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Receptores da Transferrina/genética , Transferrina/genética
6.
Eur J Med Chem ; 224: 113671, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34237623

RESUMO

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the fourth leading cause of cancer-related death worldwide. First-line drugs such as sorafenib provide only a modest benefit to HCC patients. In this study, the gram-scale synthesis of 2-benzoylquinazolin-4(3H)-one skeleton was achieved successfully via the I2/DMSO catalytic system. A series of penipanoid C-inspired 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3H)-one derivatives was synthesized and evaluated for their cytotoxic activities against four cancer cell lines, HepG2, Bel-7402, A549, and U251. Among these compounds, 4a was the most effective one with IC50 values of 1.22 µM and 1.71 µM against HepG2 and Bel-7402 cells, respectively. Mechanistic studies showed that 4a inhibited hepatocellular carcinoma cell proliferation via arresting cell cycle. Additionally, 4a induced HepG2 cells apoptosis by inducing reactive oxygen species production and elevating the expression of apoptosis-related proteins. More importantly, 4a displayed significant in vivo anticancer effects in the HepG2 xenograft models. This suggests that 4a is a promising lead compound with the potential to be developed as a chemotherapy agent for hepatocellular carcinoma.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinazolinonas/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
7.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281194

RESUMO

Cockayne syndrome group A (CS-A) is a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. Cells derived from CS-A patients present as pathological hallmarks excessive oxidative stress, mitochondrial fragmentation and apoptosis associated with hyperactivation of the mitochondrial fission dynamin related protein 1 (DRP1). In this study, by using human cell models we further investigated the interplay between DRP1 and CSA and we determined whether pharmacological or genetic inhibition of DRP1 affects disease progression. Both reactive oxygen and nitrogen species are in excess in CS-A cells and when the mitochondrial translocation of DRP1 is inhibited a reduction of these species is observed together with a recovery of mitochondrial integrity and a significant decrease of apoptosis. This study indicates that the CSA-driven modulation of DRP1 pathway is key to control mitochondrial homeostasis and apoptosis and suggests DRP1 as a potential target in the treatment of CS patients.


Assuntos
Síndrome de Cockayne/metabolismo , Dinaminas/metabolismo , Mitocôndrias/metabolismo , Animais , Apoptose/genética , Linhagem Celular , Síndrome de Cockayne/fisiopatologia , Progressão da Doença , Dinaminas/genética , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/fisiologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Estresse Oxidativo , Quinazolinonas/metabolismo , Quinazolinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
8.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209117

RESUMO

Progressive loss of muscle and muscle function is associated with significant fibrosis in Duchenne muscular dystrophy (DMD) patients. Halofuginone, an analog of febrifugine, prevents fibrosis in various animal models, including those of muscular dystrophies. Effects of (+)/(-)-halofuginone enantiomers on motor coordination and diaphragm histopathology in mdx mice, the mouse model for DMD, were examined. Four-week-old male mice were treated with racemic halofuginone, or its separate enantiomers, for 10 weeks. Controls were treated with saline. Racemic halofuginone-treated mice demonstrated better motor coordination and balance than controls. However, (+)-halofuginone surpassed the racemic form's effect. No effect was observed for (-)-halofuginone, which behaved like the control. A significant reduction in collagen content and degenerative areas, and an increase in utrophin levels were observed in diaphragms of mice treated with racemic halofuginone. Again, (+)-halofuginone was more effective than the racemic form, whereas (-)-halofuginone had no effect. Both racemic and (+)-halofuginone increased diaphragm myofiber diameters, with no effect for (-)-halofuginone. No effects were observed for any of the compounds tested in an in-vitro cell viability assay. These results, demonstrating a differential effect of the halofuginone enantiomers and superiority of (+)-halofuginone, are of great importance for future use of (+)-halofuginone as a DMD antifibrotic therapy.


Assuntos
Músculo Esquelético , Distrofia Muscular de Duchenne , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Animais , Modelos Animais de Doenças , Fibrose , Masculino , Camundongos , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia
9.
Cancer Immunol Immunother ; 70(12): 3693-3700, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34173009

RESUMO

The PI3Kδ-inhibitor Idelalisib is approved for the treatment of Non-Hodgkin lymphoma. However, its use has been decreased within the last years due to deleterious infections such as cytomegalovirus and pneumocystis jirovecii. Here, we have investigated the effect of Idelalisib on human monocyte-derived dendritic cells (DCs) as important players in the induction of immune responses. We found that Idelalisib-treated DCs displayed impaired T cell stimulatory function. PI3Kδ inhibition during differentiation resulted in decreased Interleukin-12, Interleukin-13 and TNFα production by DCs after lipopolysaccharide stimulation. Moreover, DCs showed decreased expression of the activation marker CD83 after Idelalisib treatment. Further, in line with this was the failure of Idelalisib-treated DCs to properly induce allogeneic T cells in a dose-dependent manner. Finally, activation of the NFκB pathway was also ablated in Idelalisib-treated DCs. Our results implicate that severe infectious complications may not only result from direct PI3Kδ-inhibition in T cells, but also from impaired DC function in Idelalisib-treated patients. Here, we provide new insight into the pathogenesis of Idelalisib-associated infectious complications. Our study may further provide a rationale for the use of Idelalisib as a novel therapeutic option in inflammatory diseases.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Células Dendríticas/efeitos dos fármacos , Purinas/farmacologia , Quinazolinonas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células Dendríticas/metabolismo , Humanos , Imunidade/efeitos dos fármacos , Interleucina-12/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
10.
J Med Chem ; 64(13): 8951-8970, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34138567

RESUMO

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite Experimental/induzido quimicamente , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos DBA , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Relação Estrutura-Atividade
11.
Nat Commun ; 12(1): 3697, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140482

RESUMO

Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.


Assuntos
Acrilamidas/administração & dosagem , Acrilamidas/farmacologia , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/dietoterapia , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacologia , Acrilamidas/farmacocinética , Acrilamidas/toxicidade , Compostos de Anilina/farmacocinética , Compostos de Anilina/toxicidade , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Estudos de Coortes , Simulação por Computador , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Modelos Estatísticos , Modelos Teóricos , Mutação , Quinazolinonas/farmacocinética , Quinazolinonas/toxicidade
12.
Eur J Med Chem ; 222: 113609, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34119830

RESUMO

This work presents the design and synthesis of a series of new quinazolin-4-one derivatives, based on the established effectiveness of quinazoline-based small molecules as anticancer agents. Synthesized compounds were more potent against MCF-7 than A-549 with low to submicromolar IC50s. Compound 17 exhibited the best IC50 being equipotent with the positive control doxorubicin (IC50 = 0.06 µM) and better than 5-fluorouracil (IC50 = 2.13 µM). Compound 17 was further tested against MDA-MB-231 and MCF-10A and was found to be > 2 folds more cytotoxic on MCF-7. Significant apoptotic activity was elicited by 17 on MCF-7 where it increased apoptotic cell death along with induction of pre-G1 and G1-phase cell cycle arrest. Similarly, 17 was able to induce apoptosis in MD-MB-231 treated cells associated with a disruption of the cell cycle causing arrest at the pre-G1 and S phases. Investigation of gene expression in MCF-7 demonstrated an increased expression of the proapoptotic genes P53, PUMA, Bax, caspases 3, 8 and 9 and a decrease of the anti-apoptotic gene Bcl2. Also, 17 reduced autophagy giving way for apoptosis to induce cancer cells death. This latter observation was associated with downregulation of EGFR and its downstream effectors PI3K, AKT and mTor. As its biomolecular target, 17 also inhibited EGFR similar to erlotinib (IC50 = 0.072 and 0.087 µM, respectively). Additionally, in vivo testing in a mouse model of breast cancer affirmed the anti-tumor efficacy of 17. Finally, docking of 17 against EGFR ATP binding site demonstrated its ability to bind with EGFR resembling erlotinib.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Desenho de Fármacos , Quinazolinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
13.
Nat Commun ; 12(1): 3907, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162861

RESUMO

SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection.


Assuntos
COVID-19/tratamento farmacológico , Mepesuccinato de Omacetaxina/farmacologia , Piperidinas/farmacologia , Quinazolinonas/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Serina Endopeptidases/metabolismo , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/patologia , COVID-19/virologia , Células Cultivadas , Chlorocebus aethiops , Ensaios de Triagem em Larga Escala/métodos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Camundongos , Inibidores da Síntese de Proteínas/farmacologia , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/metabolismo
14.
Molecules ; 26(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071141

RESUMO

The pathogenesis of colorectal cancer is a multifactorial process. Dysbiosis and the overexpression of COX-2 and LDHA are important effectors in the initiation and development of the disease through chromosomal instability, PGE2 biosynthesis, and induction of the Warburg effect, respectively. Herein, we report the in vitro testing of some new quinoxalinone and quinazolinone Schiff's bases as: antibacterial, COX-2 and LDHA inhibitors, and anticolorectal agents on HCT-116 and LoVo cells. Moreover, molecular docking and SAR analyses were performed to identify the structural features contributing to the biological activities. Among the synthesized molecules, the most active cytotoxic agent, (6d) was also a COX-2 inhibitor. In silico ADMET studies predicted that (6d) would have high Caco-2 permeability, and %HIA (99.58%), with low BBB permeability, zero hepatotoxicity, and zero risk of sudden cardiac arrest, or mutagenicity. Further, (6d) is not a potential P-gp substrate, instead, it is a possible P-gpI and II inhibitor, therefore, it can prevent or reverse the multidrug resistance of the anticancer drugs. Collectively, (6d) can be considered as a promising lead suitable for further optimization to develop anti-CRC agents or glycoproteins inhibitors.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Quinazolinonas/farmacologia , Quinoxalinas/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/antagonistas & inibidores , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
15.
J Enzyme Inhib Med Chem ; 36(1): 1205-1216, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34074193

RESUMO

In this paper, a set of 3-methylquniazolinone derivatives were designed, synthesised, and studied the preliminary structure-activity relationship for antiproliferative activities. All target compounds performed significantly inhibitory effects against wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and tumour cells (A431, A549, MCF-7, and NCI-H1975). In particular, compound 4d 3-fluoro-N-(4-((3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)phenyl)benzamide showed higher antiproliferative activities against all tumour cells than Gefitinib (IC50 of 3.48, 2.55, 0.87 and 6.42 µM, respectively). Furthermore, compound 4d could induce apoptosis of MCF-7 cells and arrest in G2/M phase at the tested concentration. Molecular docking and ADMET studies showed that compound 4d could closely form many hydrogen bonds with EGFRwt-TK. Therefore, compound 4d is potential to develop as novel anti-cancer drug.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Ratos , Relação Estrutura-Atividade
16.
Leuk Lymphoma ; 62(11): 2679-2689, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33999745

RESUMO

Molecular targets of tyrosine kinase inhibitors are not restricted to the B-cell compartment but also regulate functions in the tumor microenvironment. Increasing evidence suggests that B-cell receptor-associated kinases like protein kinase C (PKC)-ß is essential for the formation of a microenvironment supporting leukemic growth. Here we describe the effect of Idelalisib on the PKCß/NF-κB and Notch pathway in stromal cells upon contact to primary chronic lymphocytic leukemia cells (CLL). There is no Idelalisib-dependent regulation of the Notch expression in stromal cells, whereas Idelalisib induces PKCß expression and activates the canonical NF-κB pathway. Idelalisib deregulates important immune-modulatory proteins in activated stromal cells, which might provoke the patient's side effects. Additionally, we established a 3D-stroma/leukemia model, that can give us a more defined look into the communication between tumor and stromal cells than standard cell cultures. This opens up the possibility to improve therapies, especially in the context of minimal-residual disease.


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Purinas/farmacologia , Quinazolinonas/farmacologia , Células Estromais , Microambiente Tumoral
17.
Biomed Pharmacother ; 140: 111689, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34004510

RESUMO

Vascular smooth muscle cell (VSMC) phenotypic switch plays an essential role in the pathogenesis of hypertension. Mitochondrial dynamics, such as mitochondrial fission, can also contribute to VSMC phenotypic switch. Whether mitochondrial fission act as a novel target for anti-hypertensive drug development remains unknown. In the present study, we confirmed that angiotensin II (AngII) rapidly and continuously induced mitochondrial fission in VSMCs. We also detected the phosphorylation status of dynamin-related protein-1 (Drp1), a key protein involved in mitochondrial fission, at Ser616 site; and observed Drp1 mitochondrial translocation in VSMCs or arteries of AngII-induced hypertensive mice. The Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) dramatically reversed AngII-induced Drp1 phosphorylation, mitochondrial fission, and reactive oxidative species generation. Treatment with Mdivi-1 (20 mg/kg/every other day) significantly attenuated AngII-induced hypertension (22 mmHg), arterial remodeling, and cardiac hypertrophy, in part by preventing VSMC phenotypic switch. In addition, Mdivi-1 treatment was not associated with liver or renal functional injury. Collectively, these results indicate that Mdivi-1 inhibited mitochondrial fission, recovered mitochondrial activity, and prevented AngII-induced VSMC phenotypic switch, resulting in reduced hypertension.


Assuntos
Angiotensina II/farmacologia , Hipertensão/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Quinazolinonas/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Células Cultivadas , Dinaminas/metabolismo , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
18.
J Pharmacol Sci ; 146(3): 149-159, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34030797

RESUMO

Mitochondria maintain their function by the process of mitochondrial dynamics, which involves repeated fusion and fission. It is thought that the failure of mitochondrial dynamics, especially excessive fission, is related to the progression of several diseases. A previous study demonstrated that mitochondrial fragmentation occurs in the retinal pigmented epithelial (RPE) cells of patients with non-exudative age-related macular degeneration (AMD). We predicted that the suppression of mitochondrial fragmentation offers a novel therapeutic strategy for non-exudative AMD. We investigated whether the inhibition of mitochondrial fission was effective against the oxidative stress-induced damage of ARPE-19 cells. The treatment of ARPE-19 cells with H2O2 caused mitochondrial fragmentation, but treatment with mitochondrial division inhibitor 1 (Mdivi-1) suppressed fragmentation. Additionally, Mdivi-1 protected ARPE-19 cells against H2O2-induced damage, and suppressed the release of cytochrome c from the mitochondria. Mitochondrial function was evaluated by staining with JC-1 and measuring the production of reactive oxygen species (ROS), which revealed that mitochondrial function improved in the Mdivi-1-treated group. These findings indicated that the inhibition of mitochondrial fission would be a novel therapeutic target for non-exudative AMD.


Assuntos
Degeneração Macular/tratamento farmacológico , Degeneração Macular/etiologia , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Epitélio Pigmentado da Retina/patologia , Células Cultivadas , Citocromos c/metabolismo , Humanos , Degeneração Macular/patologia , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo
19.
Nucleic Acids Res ; 49(10): 5726-5742, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34023907

RESUMO

Appropriate regulation of the Integrated stress response (ISR) and mTORC1 signaling are central for cell adaptation to starvation for amino acids. Halofuginone (HF) is a potent inhibitor of aminoacylation of tRNAPro with broad biomedical applications. Here, we show that in addition to translational control directed by activation of the ISR by general control nonderepressible 2 (GCN2), HF increased free amino acids and directed translation of genes involved in protein biogenesis via sustained mTORC1 signaling. Deletion of GCN2 reduced cell survival to HF whereas pharmacological inhibition of mTORC1 afforded protection. HF treatment of mice synchronously activated the GCN2-mediated ISR and mTORC1 in liver whereas Gcn2-null mice allowed greater mTORC1 activation to HF, resulting in liver steatosis and cell death. We conclude that HF causes an amino acid imbalance that uniquely activates both GCN2 and mTORC1. Loss of GCN2 during HF creates a disconnect between metabolic state and need, triggering proteostasis collapse.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Transdução de Sinais/genética , Estresse Fisiológico/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Códon/genética , Ontologia Genética , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Polirribossomos/metabolismo , Inibidores da Síntese de Proteínas/administração & dosagem , Inibidores da Síntese de Proteínas/farmacologia , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacologia , RNA de Transferência/genética , RNA de Transferência/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos
20.
Chem Biol Drug Des ; 98(2): 234-247, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34013660

RESUMO

The 2-aryl-2,3-dihydrobenzodiazaborinin-4(1H)-ones (azaborininone) were synthesized as analogues of the 2-arylquinazoline-4-ones and screened through enzymatic assay in vitro for inhibitory effect against α-glucosidase and α-amylase activities. These azaborininones exhibited moderate to good inhibitory effect against these enzymes compared to acarbose used as a reference standard. The results are supported by the enzyme-ligand interactions through kinetics (in vitro) and molecular docking (in silico) studies. The test compounds also exhibited significant antioxidant activity through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) free radical scavenging assays. These azaborininone derivatives exhibited no effect on the viability of the human lung cancer (A549) cell line after 24 hr and were also not toxic towards the Vero cells.


Assuntos
Antioxidantes/química , Compostos Aza/química , Inibidores Enzimáticos/química , Inibidores de Glicosídeo Hidrolases/química , Quinazolinonas/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/química , Animais , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Quinazolinonas/síntese química , Quinazolinonas/metabolismo , Quinazolinonas/farmacologia , Relação Estrutura-Atividade , Células Vero , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
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