排序方式: 共有78条查询结果,搜索用时 15 毫秒
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EA Peterson AA Boezio PS Andrews CM Boezio TL Bush AC Cheng D Choquette JR Coats AE Colletti KW Copeland M DuPont R Graceffa B Grubinska JL Kim RT Lewis J Liu EL Mullady MH Potashman K Romero PL Shaffer MK Stanton JC Stellwagen Y Teffera S Yi T Cai DS La 《Bioorganic & medicinal chemistry letters》2012,22(15):4967-4974
mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series. 相似文献
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Lam TK Carpentier A Lewis GF van de Werve G Fantus IG Giacca A 《American journal of physiology. Endocrinology and metabolism》2003,284(5):E863-E873
The associations between obesity, insulin resistance, and type 2 diabetes mellitus are well documented. Free fatty acids (FFA), which are often elevated in obesity, have been implicated as an important link in these associations. Contrary to muscle glucose metabolism, the effects of FFA on hepatic glucose metabolism and the associated mechanisms have not been extensively investigated. It is still controversial whether FFA have substantial effects on hepatic glucose production, and the mechanisms responsible for these putative effects remain unknown. We review recent progress in this area and try to clarify controversial issues regarding the mechanisms responsible for the FFA-induced increase in hepatic glucose production in the postabsorptive state and during hyperinsulinemia. 相似文献
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Lin LS Kopka IE Mumford RA Magriotis PA Lanza T Durette PL Kamenecka T Young DN de Laszlo SE McCauley E Riper GV Kidambi U Egger LA Tong X Lyons K Vincent S Stearns R Colletti A Teffera Y Fenyk-Melody J Schmidt JA MacCoss M Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(4):611-614
Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties. 相似文献
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Levy SF Leboeuf AC Massie MR Jordan MA Wilson L Feinstein SC 《The Journal of biological chemistry》2005,280(14):13520-13528
The microtubule-associated protein tau is implicated in the pathogenesis of many neurodegenerative diseases, including fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), in which both RNA splicing and amino acid substitution mutations in tau cause dominantly inherited early onset dementia. RNA-splicing FTDP-17 mutations alter the wild-type approximately 50:50 3-repeat (3R) to 4-repeat (4R) tau isoform ratio, usually resulting in an excess of 4R tau. To examine further how splicing mutations might cause dysfunction by misregulation of microtubule dynamics, we used video microscopy to determine the in vitro behavior of individual microtubules stabilized by varying amounts of human 4R and 3R tau. At low tau:tubulin ratios (1:55 and 1:45), all 3R isoforms reduced microtubule growth rates relative to the no-tau control, whereas all 4R isoforms increased them; however, at a high tau:tubulin ratio (1:20), both 4R and 3R tau increased the growth rates. Further analysis revealed two distinct subpopulations of growing microtubules in the absence of tau. Increasing concentrations of both 4R and 3R tau resulted in an increase in the size of the faster growing subpopulation of microtubules; however, 4R tau caused a redistribution to the faster growing subpopulation at lower tau:tubulin ratios than 3R tau. This modulation of discrete growth rate subpopulations by tau suggests that tau causes a conformational shift in the microtubule resulting in altered dynamics. Quantitative and qualitative differences observed between 4R and 3R tau are consistent with a "microtubule misregulation" model in which abnormal tau isoform expression results in the inability to properly regulate microtubule dynamics, leading to neuronal death and dementia. 相似文献
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Peterson EA Andrews PS Be X Boezio AA Bush TL Cheng AC Coats JR Colletti AE Copeland KW DuPont M Graceffa R Grubinska B Harmange JC Kim JL Mullady EL Olivieri P Schenkel LB Stanton MK Teffera Y Whittington DA Cai T La DS 《Bioorganic & medicinal chemistry letters》2011,21(7):2064-2070
mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC50 of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model. 相似文献
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King MD Guentzel MN Arulanandam BP Bodour AA Brahmakshatriya V Lupiani B Chambers JP 《Applied and environmental microbiology》2011,77(12):4119-4125
Proteolytic cleavage activation of influenza virus hemagglutinin (HA0) is required for cell entry via receptor-mediated endocytosis. Despite numerous studies describing bacterial protease-mediated influenza A viral activation in mammals, very little is known about the role of intestinal bacterial flora of birds in hemagglutinin cleavage/activation. Therefore, the cloaca of wild waterfowl was examined for (i) representative bacterial types and (ii) their ability to cleave in a "trypsin-like" manner the precursor viral hemagglutinin molecule (HA0). Using radiolabeled HA0, bacterial secretion-mediated trypsin-like conversion of HA0 to HA1 and HA2 peptide products was observed to various degrees in 42 of 44 bacterial isolates suggestive of influenza virus activation in the cloaca of wild waterfowl. However, treatment of uncleaved virus with all bacterial isolates gave rise to substantially reduced emergent virus progeny compared with what was expected. Examination of two isolates exhibiting pronounced trypsin-like conversion of HA0 to HA1 and HA2 peptide products and low infectivity revealed lipase activity to be present. Because influenza virus possesses a complex lipid envelope, the presence of lipid hydrolase activity could in part account for the observed less-than-expected level of viable progeny. A thorough characterization of respective isolate protease HA0 hydrolysis products as well as other resident activities (i.e., lipase) is ongoing such that the role of these respective contributors in virus activation/inactivation can be firmly established. 相似文献
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Adria LaViolette 《American anthropologist》2006,108(3):605-606
African Connections: Archaeological Perspectives on Africa and the Wider World. Peter Mitchell. New York: AltaMira Press, 2005. 307 pp. 相似文献