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1.
Eur J Immunol ; 54(1): e2350626, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37837385

RESUMO

To better understand the stoichiometry of CD95L required to trigger apoptotic and nonapoptotic signals, we generated several CD95L concatemers from dimer to hexamer conjugated via a flexible link (GGGGS)2 . These ligands reveal that although the hexameric structure is the best stoichiometry to trigger cell death, a dimer is sufficient to induce the apoptotic response in CD95-sensitive Jurkat cells. Interestingly, only trimeric and hexameric forms can implement a potent Ca2+ response, suggesting that while CD95 aggregation controls the implementation of the apoptotic signal, both aggregation and conformation are required to implement the Ca2+ pathway.


Assuntos
Apoptose , Receptor fas , Humanos , Apoptose/fisiologia , Proteína Ligante Fas , Células Jurkat
2.
Immunity ; 45(1): 209-23, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27438772

RESUMO

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.


Assuntos
Sinalização do Cálcio , Inflamação/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fosfolipase C gama/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Receptor fas/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/genética , Fosfolipase C gama/genética , Domínios e Motivos de Interação entre Proteínas/genética , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Transcriptoma , Migração Transendotelial e Transepitelial , Receptor fas/genética
3.
Bioorg Med Chem ; 69: 116851, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35753263

RESUMO

During our work on exploration of molecules with some piperidine-triazole scaffolds, we realized that our compounds display chemical similarity with some σ, as well as dopaminergic receptor ligands. Here we show that this series of molecules has indeed strong affinity both for σ1 and dopamine D4 receptors. Moreover, they appear selective towards σ2, dopamine paralogues D1, D2, D3 and D5 receptors and hERG channel. Extensive molecular dynamics with our lead compound AVRM-13 were carried out on σ1, supporting agonist activity of the ligand. Unexpectedly, several observations suggested the existence of a cation binding domain, a probable regulatory site for calcium.


Assuntos
Dopamina , Receptores sigma , Ligantes , Ligação Proteica , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D4/metabolismo , Receptores sigma/metabolismo
4.
Molecules ; 27(19)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36234686

RESUMO

Three series of our lead CLK1 inhibitor DB18 have been designed, synthetized and tested against CLKs and DYRK1A kinases. Their cytotoxicity was subsequently measured on seven representative cancer cell lines. Guided by docking experiments, we focused on the less constrained part of the scaffold, and showed that drastically different substituents can be tolerated here. This work ended with the discovery of another promising derivative 12g, with IC50 = 0.004 µM in the inhibition of HsCLK1 and IC50 = 3.94 µM for the inhibition of HsDYRK1A. The SAR results are discussed in the light of extensive molecular modeling analyses. Finally, a kinome scan (463 human kinases) confirmed the outstanding selectivity of our lead compound DB18, suggesting that this scaffold is of prominent interest for selective CLK inhibitors. Altogether, these results pave the way for the development of inhibitors with novel selectivities in this family of kinases.


Assuntos
Inibidores de Proteínas Quinases , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 52: 128390, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34601029

RESUMO

A small library of new piperidine-triazole hybrids with 3-aryl isoxazole side chains has been designed and synthesized. Their cytotoxicity against a panel of seven cancer cell lines has been established. For the most promising compound, an IC50 value of 3.8 µM on PUMA/Bcl-xL interaction in live cancer cells was established through BRET analysis. A rationale was proposed for these results through complete molecular modelling studies.


Assuntos
Antineoplásicos/farmacologia , Isoxazóis/farmacologia , Piperidinas/farmacologia , Triazóis/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 , Isoxazóis/química , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
6.
Org Biomol Chem ; 19(41): 8968-8987, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34596646

RESUMO

In the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel of in cellulo biological studies, allowing the identification of dual Bcl-xL/Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure-activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1 versus Bcl-xL.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides
7.
Bioorg Med Chem ; 31: 115962, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422908

RESUMO

We describe in this paper the synthesis of a novel series of anilino-2-quinazoline derivatives. These compounds have been screened against a panel of eight mammalian kinases and in parallel they were tested for cytotoxicity on a representative panel of seven cancer cell lines. One of them (DB18) has been found to be a very potent inhibitor of human "CDC2-like kinases" CLK1, CLK2 and CLK4, with IC50 values in the 10-30 nM range. Interestingly, this molecule is inactive at 100 µM on the closely related "dual-specificity tyrosine-regulated kinase 1A" (DYRK1A). Extensive molecular simulation studies have been performed on the relevant kinases to explain the strong affinity of this molecule on CLKs, as well as its selectivity against DYRK1A.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , 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 Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Quinases Dyrk
8.
Nat Chem Biol ; 14(12): 1079-1089, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30429604

RESUMO

CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca2+ response via docking of PLCγ1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLCγ1 interaction. A structure-activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLCγ1. Thus, we synthesized CID peptidomimetics abrogating both the CD95-driven Ca2+ response and transmigration of Th17 cells. Injection of ritonavir and the CID peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients.


Assuntos
Inflamação/prevenção & controle , Peptidomiméticos/farmacologia , Fosfolipase C gama/metabolismo , Células Th17/efeitos dos fármacos , Receptor fas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/etiologia , Masculino , Camundongos Mutantes , Simulação de Acoplamento Molecular , Peptidomiméticos/química , Fosfolipase C gama/genética , Domínios Proteicos , Ritonavir/química , Ritonavir/farmacologia , Relação Estrutura-Atividade , Células Th17/metabolismo , Células Th17/patologia , Tiazóis/química , Tiazóis/farmacologia , Receptor fas/genética
9.
Bioorg Med Chem Lett ; 29(21): 126669, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526605

RESUMO

Proceeding our effort to study protein-protein interaction between the death receptor CD95 and phospholipase PLCγ1, we present in the current work chameleon-like traits of peptidomimetic inhibitors. Minute analysis of the interaction suggests that most of the binding energy relies on van der Waals contacts rather than more specific features, such as hydrogen bonds or salt bridges. The two most important positions of the peptoid for its interaction with PLCγ1 (Arg184 and Arg187) were modified to test this hypothesis. While Arg184 proves to be exchangeable for Trp, with no alteration in affinity, the nature of the amino acid replacing Arg187 is more dependent on its positive charge. However, affinity can be partially recovered by increasing van der Waals interactions. Overall, this study shows that for both positions, a subtle balance exists between hydrophobicity, surface contacts and affinity for CD95/PLCγ1, and provides information for the generation of new therapeutic compounds toward this druggable target.


Assuntos
Fosfolipase C gama/química , Receptor fas/química , Sequência de Aminoácidos , Arginina/química , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Eletricidade Estática , Propriedades de Superfície , Termodinâmica
10.
Bioorg Med Chem Lett ; 29(16): 2094-2099, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301931

RESUMO

The death receptor CD95 (also known as Fas) induces apoptosis through protein/protein association and the formation of the death-inducing signaling complex. On the other hand, in certain biological conditions, this receptor recruits different proteins and triggers the formation of another complex designated motility-inducing signaling complex, which promotes cell migration and inflammation. This pathway relies on a short sequence of CD95, called calcium-inducing domain (CID), which interacts with the phospholipase PLCγ1. To better understand how CID/PLCγ1 interaction occurs, we synthesized different α-AA peptides mimicking CID. Some of these peptidomimetics are as potent as the natural peptide to disrupt the CID/PLCγ1 interaction and cell migration, and showed improved pharmacokinetic properties. We also generated biotinyl- and palmitoyl-labelled peptidomimetics, useful chemico-biological tools to further explore the pro-inflammatory signal of CD95, which plays an important role in the pathogenesis of lupus and other autoimmune diseases.


Assuntos
Peptidomiméticos/farmacologia , Fosfolipase C gama/metabolismo , Multimerização Proteica/efeitos dos fármacos , Receptor fas/metabolismo , Biotina/análogos & derivados , Biotina/metabolismo , Biotina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Ligação Proteica
11.
Bioorg Med Chem Lett ; 26(21): 5263-5266, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27692832

RESUMO

Synthesis and biological evaluation of a new class of histamine H4 receptor ligands, distinct from the previously reported chemotypes, are described. A virtual screening of our corporate compound collection identified a hit with an undesired dual H3R/H4R activity. Chemical exploration led to the discovery of a more potent and selective 2-benzothiazolylphenylmethyl ether lead compound.


Assuntos
Benzotiazóis/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Benzotiazóis/química , Benzotiazóis/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Receptores Histamínicos , Receptores Histamínicos H4
12.
Bioorg Med Chem Lett ; 26(3): 885-888, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26723530

RESUMO

The seminal human dopamine D3 receptor (hD3R) ligand BP 897 has shown interesting properties during clinical trials. However, its lack of selectivity towards human adrenergic receptor impedes further development. Two approaches were followed to increase hD3R selectivity. The lead optimisation succeeded, we disclose here ligands with subnanomolar potency for D3R, combined with a good selectivity for the closely related human dopamine D2 and human adrenergic alpha-1 receptors.


Assuntos
Ligantes , Receptores de Dopamina D3/química , Sítios de Ligação , Humanos , Cinética , Simulação de Acoplamento Molecular , Piperazinas/química , Piperazinas/metabolismo , Estrutura Terciária de Proteína , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D3/metabolismo , Relação Estrutura-Atividade
13.
Bioorg Med Chem ; 23(8): 1747-57, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25797160

RESUMO

Inhibition of Bcl-2 family protein-protein interactions (PPI) is a very promising direction in cancer chemotherapy. Hence over the last decade, many medicinal chemistry studies endeavoured to discover drug candidates, and a wealth of chemical scaffolds with striking chemical diversity was reported as Bcl-xL inhibitors. This raises the question of whether all these molecules could occupy a unique binding site, or rather discrete pockets of the protein surface. To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors.


Assuntos
Desenho de Fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Simulação por Computador , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica , Relação Estrutura-Atividade , Proteína bcl-X/química
14.
Bioorg Med Chem Lett ; 24(7): 1758-61, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24602902

RESUMO

We describe the synthesis of a series of new molecules containing phenol and triazoles moieties, compounds which have been evaluated for their ability to inhibit Bax/Bcl-xL interactions in cancer cells, by using BRET assays, and to induce cell death. Several derivatives exhibit a very promising activity, being more potent than the reference compounds acylpyrogallol A and ABT-737. These preliminary results demonstrate that derivatives of this family can be attractive to develop new molecules with potent anticancer activity.


Assuntos
Desenho de Fármacos , Fenóis/farmacologia , Triazóis/farmacologia , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína bcl-X/antagonistas & inibidores , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
15.
J Biol Chem ; 287(6): 4041-52, 2012 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-22167199

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (B(a)P) are widely distributed environmental contaminants, known as potent ligands of the aryl hydrocarbon receptor (AhR). These chemicals trigger an early and transient increase of intracellular calcium concentration ([Ca(2+)](i)), required for AhR-related effects of PAHs. The mechanisms involved in this calcium mobilization were investigated in the present study. We demonstrated that B(a)P-mediated [Ca(2+)](i) induction was prevented in endothelial HMEC-1 cells by counteracting ß2-adrenoreceptor (ß2ADR) activity using pharmacological antagonists, anti-ß2ADR antibodies, or siRNA-mediated knockdown of ß2ADR expression; by contrast, it was strongly potentiated by ß2ADR overexpression in human kidney HEK293 cells. B(a)P was shown, moreover, to directly bind to ß2ADR, as assessed by in vitro binding assays and molecular modeling. Pharmacological inhibition and/or siRNA-mediated silencing of various signaling actors acting downstream of ß2ADR in a sequential manner, such as G protein, adenylyl cyclase, Epac-1 protein, and inositol 1,4,5-trisphosphate (IP(3))/IP(3) receptor, were next demonstrated to prevent B(a)P-induced calcium signal. Inhibition or knockdown of these signaling elements, as well as the use of chemical ß-blockers, were finally shown to counteract B(a)P-mediated induction of cytochrome P-450 1B1, a prototypical AhR target gene. Taken together, our results show that B(a)P binds directly to ß2ADR and consequently utilizes ß2ADR machinery to mobilize [Ca(2+)](i), through activation of a G protein/adenylyl cyclase/cAMP/Epac-1/IP(3) pathway. This ß2ADR-dependent signaling pathway activated by PAHs may likely be crucial for PAH-mediated up-regulation of AhR target genes, thus suggesting a contribution of ß2ADR to the health-threatening effects of these environmental pollutants.


Assuntos
Adenilil Ciclases/metabolismo , Poluentes Atmosféricos/farmacologia , Benzo(a)pireno/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Células Endoteliais/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Inositol 1,4,5-Trifosfato/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Adenilil Ciclases/genética , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Sinalização do Cálcio/genética , Citocromo P-450 CYP1B1 , Técnicas de Silenciamento de Genes , Fatores de Troca do Nucleotídeo Guanina/genética , Células HEK293 , Humanos , Inositol 1,4,5-Trifosfato/genética , Ligação Proteica , Receptores Adrenérgicos beta 2/genética , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo
16.
Bioorg Med Chem Lett ; 23(9): 2548-54, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23535326

RESUMO

Synthesis and biological evaluation of potent histamine H3 receptor antagonists incorporating a hydroxyl function are described. Compounds in this series exhibited nanomolar binding affinities for human receptor, illustrating a new possible component for the H3 pharmacophore. As demonstrated with compound BP1.4160 (cyclohexanol 19), the introduction of an alcohol function counter-intuitively allowed to reach high in vivo efficiency and favorable pharmacokinetic profile with reduced half-life.


Assuntos
Cicloexanóis/química , Etanol/química , Antagonistas dos Receptores Histamínicos H3/química , Ligantes , Receptores Histamínicos H3/química , Animais , Sítios de Ligação , Cicloexanóis/síntese química , Cicloexanóis/farmacocinética , Agonismo Inverso de Drogas , Meia-Vida , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética
17.
Bioorg Med Chem ; 21(15): 4526-9, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23787288

RESUMO

Due to its involvement in major CNS functions, the histamine H3 receptor (H3R) is the subject of intensive medicinal chemistry investigation, supported by the range of modern drug discovery tools, such as receptor modeling and ligand docking. Although the receptor models described to date share a majority of common traits, they display discrete alternatives in amino-acid conformation, rendering ligand binding modes quite different. Such variations impede structure-based drug design in the H3R field. In the present study, we used a combination of medicinal chemistry, receptor-guided and ligand-based methods to elucidate the binding mode of antagonists. The approaches converged towards a ligand orientation perpendicular to the membrane plane, bridging Glu206 of the transmembrane helix 5 to acidic amino acids of the extracellular loops. This consensus will help future structure-based drug design for H3R ligands.


Assuntos
Aminoácidos/metabolismo , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/química , Sequência de Aminoácidos , Desenho de Fármacos , Descoberta de Drogas , Ligantes , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Ligação Proteica , Receptores Histamínicos H3/metabolismo
18.
Cell Death Dis ; 13(10): 895, 2022 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-36274061

RESUMO

CD95 is a death receptor that can promote oncogenesis through molecular mechanisms that are not fully elucidated. Although the mature CD95 membrane receptor is considered to start with the arginine at position 17 after elimination of the signal peptide, this receptor can also be cleaved by MMP7 upstream of its leucine at position 37. This post-translational modification occurs in cancer cells but also in normal cells such as peripheral blood leukocytes. The non-cleaved CD95 amino-terminal region consists in a disordered domain and its in silico reconstitution suggests that it might contribute to receptor aggregation and thereby, regulate the downstream death signaling pathways. In agreement with this molecular modeling analysis, the comparison of CD95-deficient cells reconstituted with full-length or N-terminally truncated CD95 reveals that the loss of the amino-terminal region of CD95 impairs the initial steps of the apoptotic signal while favoring the induction of pro-survival signals, including the PI3K and MAPK pathways.


Assuntos
Metaloproteinase 7 da Matriz , Receptor fas , Receptor fas/genética , Receptor fas/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Apoptose/fisiologia , Leucina , Fosfatidilinositol 3-Quinases/metabolismo , Sinais Direcionadores de Proteínas , Arginina
19.
Bioorg Med Chem Lett ; 21(18): 5378-83, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21802950

RESUMO

Pre-clinical investigation of some aryl-piperidinyl ether histamine H3 receptor antagonists revealed a strong hERG binding. To overcome this issue, we have developed a QSAR model specially dedicated to H3 receptor ligands. This model was designed to be directly applicable in medicinal chemistry with no need of molecular modeling. The resulting recursive partitioning trees are robust (80-85% accuracy), but also simple and comprehensible. A novel promising lead emerged from our work and the structure-activity relationships are presented.


Assuntos
Éteres/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Transativadores/antagonistas & inibidores , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Éteres/síntese química , Éteres/química , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Estereoisomerismo , Transativadores/metabolismo , Regulador Transcricional ERG
20.
Bioorg Med Chem Lett ; 21(18): 5384-8, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21783360

RESUMO

Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for potential clinical evaluation.


Assuntos
Cicloexilaminas/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Transativadores/antagonistas & inibidores , Animais , Cicloexilaminas/síntese química , Cicloexilaminas/química , Relação Dose-Resposta a Droga , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Humanos , Ligantes , Camundongos , Modelos Moleculares , Estrutura Molecular , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Transativadores/metabolismo , Regulador Transcricional ERG
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