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1.
Trends Pharmacol Sci ; 40(2): 128-141, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30612715

RESUMO

Cancer cell dormancy is a process whereby cells enter reversible cell cycle arrest, termed quiescence. Quiescence is essential for cancer cells to acquire additional mutations, to survive in a new environment and initiate metastasis, to become resistant to cancer therapy, and to evade immune destruction. Thus, dormant cancer cells are considered to be responsible for cancer progression. As we start to understand the mechanisms that enable quiescence, we can begin to develop pharmacological strategies to target dormant cancer cells. Herein, we summarize the major molecular mechanisms underlying the dormancy of disseminated tumor cells and drug-tolerant persister cells. We then analyze the current pharmacological strategies aimed (i) to keep cancer cells in the harmless dormant state, (ii) to reactivate dormant cells to increase their susceptibility to anti-proliferative drugs, and (iii) to eradicate dormant cancer cells.


Assuntos
Antineoplásicos/farmacologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Transformação Celular Neoplásica , Resistencia a Medicamentos Antineoplásicos , Humanos , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Evasão Tumoral
2.
Chem Biol Interact ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30502331

RESUMO

Neuroblastoma is a common childhood cancer with high mortality. We evaluated the capacity of the flavonoid, isoliquiritigenin (4,2',4'-trihydroxychalcone; ISL) to inhibit cellular proliferation and migration in the human neuroblastoma cell line SH-SY5Y. Incubation of cultured SH-SY5Y cells with 20-100 µM ISL decreased cell confluency (15-70%) after 24 h incubation, while 10-100 µM ISL (24 h) depleted intracellular ATP stores (15-90% vs vehicle-treated control) after 24 h incubation. ISL-mediated cell toxicity did not involve intracellular caspase 3/7 activation, externalization of phosphatidylserine on the cell membrane or stimulation of TNF and IL-1ß release, all indicating that the flavonoid did not induce apoptosis. Pre-treatment of cells with necrostatin-1, a necroptosis inhibitor, significantly restored ATP levels (ATP levels increased 12-42%) in ISL-treated neuroblastoma cells indicative of enhanced viability. By contrast, RIP1 phosphorylation status remained unchanged in cells treated with ISL although the intracellular ratio of phosphorylated/total parental RIP1 increased after ISL treatment on SH-SY5Y cells indicating that ISL decreased levels of native RIP1. In addition, ISL treatment inhibited SH-SY5Y cell migration/proliferation in a scratch assay and arrested cell cycle transition by significantly decreasing the number of cells in G0/G1 phase and increasing populations by ∼10% in S (primarily) and G2/M (lesser extent) phases. The intracellular ratio of phosphorylated/total ERK 1/2 and p38 remained unchanged after ISL treatment (up to 40 µM); ERK activation was only determined at ISL dose well above the experimental IC50 value as judged by ELISA analyses and this did not correlate with ISL cytotoxicity at lower dose <40 µM; Western blot assay confirmed the detection of phosphorylated (p-)ERK1/2 and (p-)p38 in ISL treated cells. Together the results suggest that ISL exerts anti-proliferative and cytotoxic activity on SHSY5Y cells through the loss of ATP, induction of cell cycle arrest, and cell death largely via a necroptotic mechanism in the absence of apoptotic activity.

3.
Bioorg Med Chem ; 26(22): 5852-5869, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30401502

RESUMO

Dual-specificity tyrosine phosphorylation-related kinase 1A (DYRK1A) is a dual-specificity protein kinase that catalyses phosphorylation and autophosphorylation. Higher DYRK1A expression correlates with cancer, in particular glioblastoma present within the brain. We report here the synthesis and biological evaluation of new heterocyclic diphenolic derivatives designed as novel DYRK1A inhibitors. The generation of these heterocycles such as benzimidazole, imidazole, naphthyridine, pyrazole-pyridines, bipyridine, and triazolopyrazines was made based on the structural modification of the lead DANDY and tested for their ability to inhibit DYRK1A. None of these derivatives showed significant DYRK1A inhibition but provide valuable knowledge around the importance of the 7-azaindole moiety. These data will be of use for developing further structure-activity relationship studies to improve the selective inhibition of DYRK1A.

4.
Pharmacol Res ; 134: 166-178, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29944980

RESUMO

In the field of kinase inhibitors for applications in cancer research, tubulin is emerging as a targeted cellular protein that can significantly contribute to their activities. However, investigation of kinase inhibitors beyond the kinome is an area often neglected. Herein, we describe the results of pharmacological studies using drugs targeting kinases, tubulin or both. A key finding is that if cells are treated with a kinase inhibitor unintentionally targeting tubulin, their characteristic shape will diminish within a short timeframe. These changes in cell morphology are not seen when cells are treated with bona fide kinase inhibitors that do not directly target tubulin. Thus, early changes in cell morphology upon treatments are a strong indication that the inhibitor is directly targeting tubulin. Recognizing tubulin as a target of kinase inhibitors will build confidence in the future mechanistic studies using kinase inhibitors.

5.
ACS Med Chem Lett ; 8(4): 395-400, 2017 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-28435525

RESUMO

Photoremovable protecting groups added to bioactive molecules provide spatial and temporal control of the biological effects. We present synthesis and characterization of the first photoactivatable small-molecule tubulin inhibitor. By blocking the pharmacophoric OH group on compound 1 with photoremovable 4,5-dimethoxy-2-nitrobenzyl moiety we developed the photocaged prodrug 2 that had no effect in biological assays. Short UV light exposure of the derivative 2 or UV-irradiation of cells treated with 2 resulted in fast and potent inhibition of tubulin polymerization, attenuation of cell viability, and apoptotic cell death, implicating release of the parent active compound. This study validates for the first time the photoactivatable prodrug concept in the field of small molecule tubulin inhibitors. The caged derivative 2 represents a novel tool in antitubulin approaches.

6.
Nat Rev Drug Discov ; 16(6): 424-440, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28280261

RESUMO

Kinome-wide profiling platforms have comprehensively identified the relevant kinases that are targeted by numerous protein kinase inhibitors. However, recent projects have begun to discover non-kinase targets of kinase inhibitors. These non-kinase targets can contribute to the desired or undesired activities of inhibitors, or act as silent bystanders. As a full awareness of a drug's mechanism of action is crucial for the interpretation of results and for successful preclinical and clinical drug development, these discoveries highlight the importance of understanding the pharmacology of kinase inhibitors beyond the kinome. In this Review, I discuss kinase inhibitors for which non-kinase targets have been identified and the application of emerging techniques to validate drug-target engagement in intact cells.


Assuntos
Desenho de Drogas , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/metabolismo
7.
Eur J Med Chem ; 130: 433-439, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28279849

RESUMO

Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1ß release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X7R antagonists.


Assuntos
Adamantano/farmacologia , Antidepressivos/química , Guanidinas/farmacologia , Antagonistas do Receptor Purinérgico P2X/química , Adamantano/química , Animais , Antidepressivos/farmacologia , Comportamento/efeitos dos fármacos , Descoberta de Drogas , Guanidinas/química , Camundongos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Relação Estrutura-Atividade
8.
Future Med Chem ; 9(3): 303-314, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28176536

RESUMO

Originally thought to be nondruggable, kinases represent attractive drug targets for pharmaceutical companies and academia. To date, there are over 40 kinase inhibitors approved by the US FDA, with 32 of these being small molecules, in addition to the three mammalian target of rapamycin inhibitor macrolides (sirolimus, temsirolimus and everolimus). Despite the rapid development of kinase inhibitors for cancer, presently none of these agents are approved for CNS indications. This mini perspective highlights selected kinase targets for CNS disorders, of which brain-permeable small-molecule inhibitors are reported, with demonstrated preclinical proof-of-concept efficacy. This is followed by a brief discussion on the key challenges of blood-brain barrier penetration and selectivity profiles in developing kinase inhibitors for CNS disorders.


Assuntos
Encefalopatias/tratamento farmacológico , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Humanos , Camundongos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico
9.
J Med Chem ; 60(5): 2052-2070, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28206758

RESUMO

The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC50 ≤ 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells. Target engagement was confirmed with genetic knockdown and the cellular thermal shift assay. We demonstrate that DYRK1A's thermal stability in cells is increased upon compound treatment, confirming binding in cells. In summary, we present synthesis, structure-activity relationship, and efficacy in glioblastoma-relevant models for a library of novel 7-azaindoles.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioblastoma/enzimologia , Proteínas Quinases/metabolismo , Tirosina/metabolismo , Humanos , Fosforilação , Relação Estrutura-Atividade
10.
Medchemcomm ; 8(1): 202-210, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108706

RESUMO

The 18 kDa translocator protein (TSPO) is a target for development of diagnostic imaging agents for glioblastoma and neuroinflammation. Clinical translation of TSPO imaging agents has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Disclosed brain-permeant second-generation TSPO ligands bind TSPO A147T with reduced affinity compared to the wild type protein (TSPO WT). Efforts to develop a TSPO ligand that binds TSPO WT and TSPO A147T with similarly high affinity have been hampered by a lack of knowledge about how ligand structure differentially influences interaction with the two forms of TSPO. To gain insight, we have established human embryonic kidney cell lines stably over-expressing human TSPO WT and TSPO A147T, and tested how modifications of a novel N-alkylated carbazole scaffold influence affinity to both TSPO isoforms. Most of the new analogues developed in this study showed high affinity to TSPO WT and a 5-6-fold lower affinity to TSPO A147T. Addition of electron-withdrawing substituents yielded analogues with highest affinity for TSPO A147T without decreasing affinity for TSPO WT. This knowledge can be used to inform further development of non-discriminating TSPO ligands for use as diagnostic markers for glioblastoma and neuroinflammation irrespective of rs6971.

12.
Cancer Cell ; 29(2): 145-58, 2016 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-26859455

RESUMO

Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.


Assuntos
Antineoplásicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Leucemia/tratamento farmacológico , Proteínas Mitocondriais/fisiologia , Mimetismo Molecular , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Humanos , Camundongos , Fator de Necrose Tumoral alfa/biossíntese
13.
Cancer Biol Ther ; 17(4): 355-63, 2016 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-26794430

RESUMO

Inflammation is an important factor promoting the progression of glioblastoma. In the present study we examined the contribution of Ras signaling and TNFα/IL-1ß cytokines to the development of the glioblastoma inflammatory microenvironment. Enhanced activation of Ras through de-regulated activation of receptor tyrosine kinases, such as EGFR, PDGFR and cMet, is a hallmark of the majority of glioblastomas. Glioblastoma microenvironment contains high levels of TNFα and IL-1ß, which mediate inflammation through induction of a local network of cytokines and chemokines. While many studies have focused on Ras- and TNFα/IL-1ß-driven inflammation in isolation, little is known about the co-operation between these oncogenic and microenvironment-derived stimuli. Using constitutively active HRasG12V that mimics enhanced Ras activation, we demonstrate that elevated Ras activity in glioblastoma cells leads to up-regulation of IL-6 and IL-8. Furthermore, Ras synergizes with the microenvironment-derived TNFα and IL-1ß resulting in amplified IL-6/IL-8 secretion. IL-8 secretion induced by Ras and TNFα/IL-1ß is attenuated by inhibitors targeting Erk, JNK and p38 MAPK pathways. IL-6 secretion significantly decreased upon inhibition of JNK and p38 MAPK pathways. Interestingly, although constitutively active HRasG12V does not increase basal or TNFα/IL-1ß stimulated p38 MAPK activity, HRasG12V increased the efficacy of the p38 MAPK inhibitor SB203580 to inhibit IL-1ß-induced IL-6 secretion. In summary, oncogenic Ras co-operates with the microenvironment-derived TNFα/IL-1ß to sustain inflammatory microenvironment, which was effectively attenuated via inhibition of p38 MAPK signaling.


Assuntos
Citocinas/metabolismo , Genes ras/genética , Glioblastoma/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Biochem Pharmacol ; 98(4): 587-601, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26519552

RESUMO

We recently reported that CMPD1, originally developed as an inhibitor of MK2 activation, primarily inhibits tubulin polymerisation and induces apoptosis in glioblastoma cells. In the present study we provide detailed pharmacological investigation of CMPD1 analogues with improved molecular properties. We determined their anti-cancer efficacy in glioblastoma cells with enhanced EGFR signalling, as deregulated EGFR often leads to chemoresistance. Eight analogues of CMPD1 with varying lipophilicity and basicity were synthesised and tested for efficacy in the cell viability assay using established glioblastoma cell lines and patient-derived primary glioblastoma cells. The mechanism of action for the most potent analogue 15 was determined using MK2 activation and tubulin polymerisation assays, together with the immunofluorescence analysis of the mitotic spindle formation. Apoptosis was analysed by Annexin V staining, immunoblotting analysis of bcl-2 proteins and PARP cleavage. The apoptotic activity of CMPD1 and analogue 15 was comparable across glioblastoma cell lines regardless of the EGFR status. Primary glioblastoma cells of the classical subtype that are characterized by enhanced EGFR activity were most sensitive to the treatment with CMPD1 and 15. In summary, we present mechanism of action for a novel small molecule tubulin inhibitor, compound 15 that inhibits tubulin polymerisation and mitotic spindle formation, induces degradation of anti-apoptotic bcl-2 proteins and leads to apoptosis of glioblastoma cells. We also demonstrate that the enhanced EGFR activity does not decrease the efficacy of tubulin inhibitors developed in this study.


Assuntos
Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Transdução de Sinais/fisiologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Moduladores de Tubulina/química
15.
ChemistryOpen ; 4(1): 2017 Apr, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25861571

RESUMO

p38α mitogen-activated protein kinase (MAPK) plays a role in several cellular processes and consequently has been a therapeutic target in inflammatory diseases, cancer, and cardiovascular disease. A number of known p38α MAPK inhibitors contain vicinal 4-fluorophenyl/4-pyridyl rings connected to either a 5- or 6-membered heterocycle. In this study, a small library of substituted thiophene-based compounds bearing the vicinal 4-fluorophenyl/4-pyridyl rings was designed using computational docking as a visualisation tool. Compounds were synthesised and evaluated in a fluorescence polarisation binding assay. The synthesised analogues had a higher binding affinity to the active phosphorylated form of p38α MAPK than the inactive nonphosphorylated form of the protein. 4-(2-(4-fluorophenyl)thiophen-3-yl)pyridine had a K i value of 0.6 µm to active p38α MAPK highlighting that substitution of the core ring to a thiophene retains affinity to the enzyme and can be utilised in p38α MAPK inhibitors. This compound was further elaborated using a substituted phenyl ring in order to probe the second hydrophobic pocket. Many of these analogues exhibited low micromolar affinity to active p38α MAPK. The suppression of neonatal rat fibroblast collagen synthesis was also observed suggesting that further development of these compounds may lead to potential therapeutics having cardioprotective properties.

16.
Eur J Med Chem ; 95: 29-34, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25791676

RESUMO

LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM; 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 µM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show anti-neuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti-neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL-1ß stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes.


Assuntos
Anti-Inflamatórios/farmacologia , Benzodiazepinonas/farmacologia , Glioma/tratamento farmacológico , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Anti-Inflamatórios/química , Benzodiazepinonas/química , Células Cultivadas , Glioma/enzimologia , Glioma/patologia , Humanos , Inflamação/enzimologia , Inflamação/patologia , Interleucina-1beta/farmacologia , Interleucina-6/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Microglia/citologia , Microglia/enzimologia , Modelos Biológicos , Pirimidinas/química
17.
Pharmacol Ther ; 151: 87-98, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25795597

RESUMO

Protein kinases are one of the most studied drug targets in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. Dual-specificity Tyrosine phosphorylation-Regulated Kinase 1A (DYRK1A) has been much less studied compared to many other kinases. DYRK1A primary function occurs during early development, where this protein regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells. Although most extensively characterised for its role in brain development, DYRK1A is over-expressed in a variety of diseases including a number of human malignancies, such as haematological and brain cancers. Here we review the accumulating molecular studies that support our understanding of how DYRK1A signalling could underlie these pathological functions. The relevance of DYRK1A in a number of diseases is also substantiated with intensive drug discovery efforts to develop potent and selective inhibitors of DYRK1A. Several classes of DYRK1A inhibitors have recently been disclosed and some molecules are promising leads to develop DYRK1A inhibitors as drugs for DYRK1A-dependent diseases.


Assuntos
Neoplasias/enzimologia , Doenças Neurodegenerativas/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Processamento Alternativo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Apoptose , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Ciclo Celular , Diferenciação Celular , Síndrome de Down/tratamento farmacológico , Síndrome de Down/enzimologia , Ativação Enzimática , Dosagem de Genes , Harmina/farmacologia , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Receptores Notch/metabolismo , Transdução de Sinais
18.
Mol Pharmacol ; 85(2): 345-56, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24296859

RESUMO

Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK-2 or MK2) is a downstream substrate of the p38 MAPK responsible for the signaling events influencing inflammation, cell division and differentiation, apoptosis, and cell motility in response to a wide range of extracellular stimuli. After the failure of p38 MAPK inhibitors in clinical trials, MK2 was unveiled as a potential target to regulate inflammatory cytokines' mRNA stability and translation. Recent work suggests that this mechanism may underlie the pathophysiology of brain disorders associated with inflammation. In addition, MK2 is a prominent kinase that phosphorylates heat shock protein 27 (Hsp27), an intensively investigated biomarker of cancer progression. This phosphorylation decreases the chaperone properties of Hsp27, making MK2 an endogenous inhibitor of Hsp27. MK2 is also one of the major players in the signal transduction pathways activated in response to DNA damage. Experimental evidence highlights the role of MK2 in G(2)/M and the mitotic spindle checkpoints, two mechanisms by which MK2 contributes to the maintenance of genomic stability. Thus, MK2 is considered a good molecular target to increase, in combination with chemotherapeutic agents, the sensitivity of treatment, especially in p53-mutated tumors. This review looks at the functions of MK2 in inflammation, Hsp27 regulation, and cell cycle checkpoint control with a focus on brain pathologies. Analysis of MK2 signaling in various disease models and a summary of the data on MK2 inhibitors suggest novel indications for MK2 inhibitors in addition to their mainstream use against peripheral inflammatory disorders.


Assuntos
Ciclo Celular , Proteínas de Choque Térmico HSP27/metabolismo , Inflamação/etiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Doenças Neurodegenerativas/imunologia , Proteínas Serina-Treonina Quinases/fisiologia , Actinas/química , Animais , Movimento Celular , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/química , Fosforilação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
19.
Bioorg Med Chem ; 21(23): 7309-29, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24145137

RESUMO

3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4ß2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4ß2(∗) nAChR. All evaluated compounds are partial agonists or antagonists at α4ß2(∗), with reduced or no effects on α3ß4(∗) with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.


Assuntos
Alcanos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/química , Receptores Nicotínicos/metabolismo , Alcanos/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Camundongos , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/química , Relação Estrutura-Atividade
20.
Bioorg Med Chem ; 21(23): 7283-308, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24156938

RESUMO

3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4ß2(∗) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4ß2(∗) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.


Assuntos
Alcanos/química , Compostos Bicíclicos com Pontes/química , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/química , Receptores Nicotínicos/metabolismo , Alcanos/farmacologia , Animais , Compostos Bicíclicos com Pontes/farmacologia , Bovinos , Linhagem Celular , Ligações de Hidrogênio , Ligantes , Camundongos , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Ratos , Receptores Nicotínicos/química , Relação Estrutura-Atividade , Torpedo , Xenopus
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