Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is ...implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
A mechanistic model accounting for reduced structural reorganization and densification in the microstructure of geopolymer gels with high concentrations of soluble silicon in the activating solution ...has been proposed. The mechanical strength and Young's modulus of geopolymers synthesized by the alkali activation of metakaolin with Si/Al ratio between 1.15 and 2.15 are correlated with their respective microstructures through SEM analysis. The microstructure of specimens is observed to be highly porous for Si/Al ratios ≤1.40 but largely homogeneous for Si/Al ≥1.65, and mechanistic arguments explaining the change in microstructure based on speciation of the alkali silicate activating solutions are presented. All specimens with a homogeneous microstructure exhibit an almost identical Young's modulus, suggesting that the Young's modulus of geopolymers is determined largely by the microstructure rather than simply through compositional effects as has been previously assumed. The strength of geopolymers is maximized at Si/Al
=
1.90. Specimens with higher Si/Al ratio exhibit reduced strength, contrary to predictions based on compositional arguments alone. The decrease in strength with higher silica content has been linked to the amount of unreacted material in the specimens, which act as defect sites. This work demonstrates that the microstructures of geopolymers can be tailored for specific applications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells ...and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.
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The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a ...drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.
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Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly ...deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
reaction: see text Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two ...stereocenters are created by the reaction, and a single isomeric product was obtained from each of the five substrates examined. The relative configurations of the products are consistent with cyclizations occurring via chairlike or pseudochairlike transition states.
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Synthetic approaches are described for the synthesis of 4-alkoxyindole-7-carboxamides and 4-alkoxy-3-cyanoindole-7-carboxamides, which are useful intermediates in medicinal chemistry research. Two ...strategies were employed, highlighted by a Bartoli indole synthesis or a sequential and regioselective use of chlorosulfonyl isocyanate to install both the 3-cyano and 7-carboxamido groups. These routes are scalable and afford diversely functionalized indoles for further elaboration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were ...suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The SAR results from this investigation will be presented with an emphasis on the impact structural changes have on the cellular phenotype.
Novel Aurora inhibitors were identified truncating clinical ...candidate GSK1070916. Many of these truncated compounds retained potent activity against Aurora B with good antiproliferative activity. Mechanistic studies suggested that these compounds, depending on the substitution pattern, may or may not exert their antiproliferative effects via inhibition of Aurora B. The SAR results from this investigation will be presented with an emphasis on the impact structural changes have on the cellular phenotype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial revealed no significant differences among 1587 symptomatic heart failure patients randomized to ...warfarin, clopidogrel, or aspirin in time to all-cause death, nonfatal myocardial infarction, or nonfatal stroke. We compared within-trial medical resource use and costs between treatments. Methods and Results We assigned country-specific costs to medical resources incurred during follow-up. Annualized rates of hospitalizations, inpatient and outpatient procedures, and emergency department visits did not differ significantly between groups. Annualized total costs averaged $5901 (95% confidence interval CI, $4776-$7520) for the aspirin group, $5646 (95% CI, $4903-$6584) for the clopidogrel group, and $5830 (95% CI, $4838-$7400) for the warfarin group. Conclusions Consistent with clinical findings, our analyses did not identify significant cost differences between treatments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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