共查询到20条相似文献,搜索用时 15 毫秒
1.
Swahn BM Huerta F Kallin E Malmström J Weigelt T Viklund J Womack P Xue Y Ohberg L 《Bioorganic & medicinal chemistry letters》2005,15(22):5095-5099
The structure-based design and synthesis of a new series of c-Jun N-terminal kinase-3 inhibitors with selectivity against JNK1 and p38alpha is reported. The novel series of substituted 6-anilinoindazoles were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of the compounds crystallized into the JNK3 ATP binding active site. 相似文献
2.
Mi-hyun Kim Junghun Lee Kyungjin Jung Minjung Kim Yun-Jin Park Heechul Ahn Young Hye Kwon Jung-Mi Hah 《Bioorganic & medicinal chemistry》2013,21(8):2271-2285
1-Heteroaryl-2-aryl-1H-benzimidazole derivatives were synthesized as inhibitors of c-Jun N-terminal kinases, JNK3. Their activities were evaluated through measurement of Kd using SPR, JNK3 kinase assay, and cell-viability of human neuroblastoma cells. Most tested compounds showed high affinity (10 μM–46 nM) to JNK3. Among them, compound 16f exhibited potent activities (Kd = 46 nM). Especially, 16f was also found to present a potent cell protective effect (IC50 = 1.09 μM) against toxicity induced by anisomycin, showing a possibility as protective therapeutics in neuronal cell apoptosis. 相似文献
3.
Jiang R Duckett D Chen W Habel J Ling YY LoGrasso P Kamenecka TM 《Bioorganic & medicinal chemistry letters》2007,17(22):6378-6382
The structure-based design and synthesis of a novel series of c-Jun N-terminal kinase (JNK) inhibitors with selectivity against p38 is reported. The unique structure of 3,5-disubstituted quinolines (2) was developed from the previously reported 4-(2,7-phenanthrolin-9-yl)phenol (1). The X-ray crystal structure of 16a in JNK3 reveals an unexpected binding mode for this new scaffold with protein. 相似文献
4.
Song X Chen W Lin L Ruiz CH Cameron MD Duckett DR Kamenecka TM 《Bioorganic & medicinal chemistry letters》2011,21(23):7072-7075
The design and synthesis of a novel series of c-jun N-terminal kinase (JNK3) inhibitors is described. The development and optimization of the 2-phenoxypyridine series was carried out from an earlier pyrimidine series of JNK1 inhibitors. Through the optimization of the scaffold 2, several potent compounds with good in vivo profiles were discovered. 相似文献
5.
De SK Barile E Chen V Stebbins JL Cellitti JF Machleidt T Carlson CB Yang L Dahl R Pellecchia M 《Bioorganic & medicinal chemistry》2011,19(8):2582-2588
We report comprehensive structure-activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. Intriguingly, the compounds have a dual inhibitory activity by functioning as both ATP and JIP mimetics, possibly by binding to both the ATP binding site and to the docking site of the kinase. Several of such novel compounds display potent JNK inhibitory profiles both in vitro and in cell. 相似文献
6.
Swahn BM Xue Y Arzel E Kallin E Magnus A Plobeck N Viklund J 《Bioorganic & medicinal chemistry letters》2006,16(5):1397-1401
The design and synthesis of a new series of c-Jun N-terminal kinase-3 (JNK3) inhibitors with selectivity against JNK1 are reported. The novel series of substituted 2'-anilino-4,4'-bipyridines were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of compounds crystallized into the JNK3 ATP binding active site. 相似文献
7.
Stocks MJ Barber S Ford R Leroux F St-Gallay S Teague S Xue Y 《Bioorganic & medicinal chemistry letters》2005,15(14):3459-3462
The design and synthesis of a new series of c-Jun N-terminal kinase inhibitors are reported. The novel series of substituted amino indazoles were designed based on a combination of hits from high-throughput screening and X-ray crystal structure information of the compounds crystallised into the JNK-1 ATP binding site. 相似文献
8.
Alam M Beevers RE Ceska T Davenport RJ Dickson KM Fortunato M Gowers L Haughan AF James LA Jones MW Kinsella N Lowe C Meissner JW Nicolas AL Perry BG Phillips DJ Pitt WR Platt A Ratcliffe AJ Sharpe A Tait LJ 《Bioorganic & medicinal chemistry letters》2007,17(12):3463-3467
The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. 相似文献
9.
《Bioorganic & medicinal chemistry》2014,22(21):6209-6219
Mitogen activated protein kinases including c-Jun N-terminal kinase play an indispensable role in inflammatory diseases. Investigation of reported JNK-1 inhibitors indicated that diverse heterocyclic compounds bearing an amide group rendered potent JNK-1 inhibitory activity which prompted us to synthesize new JNK-1 inhibitors containing a pyrazole heterocyclic group. A DABCO mediated 1,3-dipolar cycloaddition reaction in neat resulted in pyrazole carboxylic acid which was converted to desired amides. Upon confirmation of the structures, all the compounds were screened for JNK-1 inhibitory activity and in vivo anti-inflammatory activity. Several synthesized analogues have exhibited JNK-1 inhibitory activity less than 10 μM, in particular compounds 9c, 10a and 10d were found to be potent among all the compounds. 相似文献
10.
Liu G Zhao H Liu B Xin Z Liu M Kosogof C Szczepankiewicz BG Wang S Clampit JE Gum RJ Haasch DL Trevillyan JM Sham HL 《Bioorganic & medicinal chemistry letters》2006,16(22):5723-5730
The structure-activity relationships of 5,6-positions of aminopyridine carboxamide-based c-Jun N-terminal Kinase (JNK) inhibitors were explored to expand interaction with the kinase specificity and ribose-binding pockets. The syntheses of analogues and the impact of structural modification on in vitro potency and cellular activity are described. 相似文献
11.
Fucini RV Hanan EJ Romanowski MJ Elling RA Lew W Barr KJ Zhu J Yoburn JC Liu Y Fahr BT Fan J Lu Y Pham P Choong IC VanderPorten EC Bui M Purkey HE Evanchik MJ Yang W 《Bioorganic & medicinal chemistry letters》2008,18(20):5648-5652
A series of 2-amino-pyrazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors based on a low micromolar hit. The SAR was developed to provide compounds exhibiting low nanomolar inhibitory activity of Plk1; the phenotype of treated cells is consistent with Plk1 inhibition. A co-crystal structure of one of these compounds with zPlk1 confirms an ATP-competitive binding mode. 相似文献
12.
Surya K. De Vida Chen John L. Stebbins Li-Hsing Chen Jason F. Cellitti Thomas Machleidt Elisa Barile Megan Riel-Mehan Russell Dahl Li Yang Aras Emdadi Ria Murphy Maurizio Pellecchia 《Bioorganic & medicinal chemistry》2010,18(2):590-596
A series of thiadiazole derivatives has been designed as potential allosteric, substrate competitive inhibitors of the protein kinase JNK. We report on the synthesis, characterization and evaluation of a series of compounds that resulted in the identification of potent and selective JNK inhibitors targeting its JIP-1 docking site. 相似文献
13.
Paul S. Humphries Jennifer A. Lafontaine Charles S. Agree David Alexander Ping Chen Quyen-Quyen T. Do Lilian Y. Li Elizabeth A. Lunney Ranjan J. Rajapakse Karen Siegel Sergei L. Timofeevski Tianlun Wang David M. Wilhite 《Bioorganic & medicinal chemistry letters》2009,19(8):2099-2102
The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported. 相似文献
14.
Surya K. De Li-Hsing Chen John L. Stebbins Thomas Machleidt Megan Riel-Mehan Russell Dahl Vida Chen Hongbin Yuan Elisa Barile Aras Emdadi Ria Murphy Maurizio Pellecchia 《Bioorganic & medicinal chemistry》2009,17(7):2712-2717
A new series of 2-thioether-benzothiazoles has been synthesized and evaluated for JNK inhibition. The SAR studies led to the discovery of potent, allosteric JNK inhibitors with selectivity against p38. 相似文献
15.
c-Jun N-terminal kinase pathways in diabetes 总被引:1,自引:0,他引:1
Yang R Trevillyan JM 《The international journal of biochemistry & cell biology》2008,40(12):2702-2706
Type 2 diabetes develops from insulin resistance and has become a worldwide epidemic. The c-Jun N-terminal kinases have been considered as signaling molecules linking inflammation and insulin resistance. Genetic disruption of c-Jun N-terminal kinase-1 gene prevents the development of insulin resistance in obese and diabetic mice. Inhibition of c-Jun N-terminal kinases by a small cell-permeable peptide improves insulin sensitivity in mice. Hepatic inhibition of c-Jun N-terminal kinases using a dominant-negative protein or knockdown of c-Jun N-terminal kinase-1 gene by RNA interference reduces blood glucose and insulin levels and enhances hepatic insulin signaling in mice. Recent evidence demonstrates that the hepatic c-Jun N-terminal kinase pathway plays an important role in lipid and lipoprotein homeostasis in mice. This review discusses recent advances in our understanding of the role of c-Jun N-terminal kinase pathway in metabolic control and its potential as a target for the treatment of type 2 diabetes. 相似文献
16.
Noncanonical function of MEKK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase signaling 下载免费PDF全文
MEKK2 and MEK5 encode Phox/Bem1p (PB1) domains that heterodimerize with one another. MEKK2, MEK5, and extracellular signal-related kinase 5 (ERK5) form a ternary complex through interactions involving the MEKK2 and MEK5 PB1 domains and a 34-amino-acid C-terminal extension of the MEK5 PB1 domain. This C-terminal extension encodes an ERK5 docking site required for MEK5 activation of ERK5. The PB1 domains bind in a front-to-back arrangement, with a cluster of basic amino acids in the front of the MEKK2 PB1 domain binding to the back-end acidic clusters of the MEK5 PB1 domain. The C-terminal moiety, including the acidic cluster of the MEKK2 PB1 domain, is not required for MEK5 binding and binds MKK7. Quiescent MEKK2 preferentially binds MEK5, and MEKK2 activation results in ERK5 activation. Activated MEKK2 binds and activates MKK7, leading to JNK activation. The findings define how the MEKK2 and MEK5 PB1 domains are uniquely used for differential binding of two mitogen-activated protein kinase kinases, MEK5 and MKK7, for the coordinated control of ERK5 and c-Jun N-terminal kinase activation. 相似文献
17.
Yong Zhang Seo Yoon Jung Changbae Jin Nam Doo Kim Ping Gong Yong Sup Lee 《Bioorganic & medicinal chemistry letters》2009,19(2):502-507
The involvement of μ-calpain in neurological disorders, such as stroke and Alzheimer’s disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 4-Aryl-4-oxobutanoic acid amide derivatives 4 were designed as acyclic variants of μ-calpain inhibitory chromone and quinolinone derivatives. Of the compounds synthesized, 4c-2, which possesses a 2-methoxymethoxy group at the phenyl ring and a primary amide at the warhead region most potently inhibited μ-calpain (IC50 = 0.34 μM). Our findings suggest that the 4-aryl-4-oxobutanoic acid amide derivatives should be considered as a new family of μ-calpain inhibitors. 相似文献
18.
Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3 总被引:10,自引:0,他引:10
Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase activated by associating with its neuron-specific activators p35 and p39. Analysis of cdk5(-/-) and p35(-/-) mice has demonstrated that both cdk5 and p35 are essential for neuronal migration, axon pathfinding and the laminar configuration of the cerebral cortex, suggesting that the cdk5-p35 complex may play a role in neuron survival. However, the targets of cdk5 that regulate neuron survival are unknown. Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation. Expression of cdk5 and p35 in HEK293T cells inhibits c-Jun phosphorylation induced by UV irradiation. These effects can be restored by expression of a catalytically inactive mutant form of cdk5. Moreover, cdk5-deficient cultured cortical neurons exhibit increased sensitivity to apoptotic stimuli, as well as elevated JNK3 activity and c-Jun phosphorylation. Taken together, these findings show that cdk5 may exert its role as a key element by negatively regulating the c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway during neuronal apoptosis. 相似文献
19.
《Bioorganic & medicinal chemistry》2020,28(19):115683
A series of 4-aryl-5-aminoalkyl-thiazole-2-amines were designed and synthesized, and their inhibitory activity on ROCK II was screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives had certain ROCK II inhibitory activities. Compound 10l showed ROCK II inhibitory activity with IC50 value of 20 nM. 相似文献
20.
Hanan EJ Fucini RV Romanowski MJ Elling RA Lew W Purkey HE VanderPorten EC Yang W 《Bioorganic & medicinal chemistry letters》2008,18(19):5186-5189
A series of 2-amino-isoxazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors. Key SAR and crystallographic data are discussed. More advanced analogues inhibit Plk1 with good enzymatic activity and modest cell-based activity. Differential selectivity among the three Plk isoforms is observed. 相似文献