AZ 10417808

AZ 10417808 is a selective caspase-3 inhibitor with IC50 value of 14.9 uM [1].
The caspase-3 protein is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis [1].
AZ 10417808 (AQZ-1) is a potent small molecule nonpeptidic inhibitor of caspase-3, which block cellular and biochemical features of apoptosis [1].
AZ 10417808 was evaluated for its inhibitory activity against caspases 1, 2, 3, 6, 7, 8 and only caspases-3 was potently inhibited. AZ 10417808 completely blocked the staurosporine-induced intracellular DEVDase activity and this effect was dose-dependent. Of control cells ( 64 ± 7%) whereas cells treated with staurosporine plus 10 μM AZ 10417808 had 92 ± 2% viability, which indicated that the AZ 10417808 enhanced cell viability in SH-SY5Y cell culture apoptosis paradigm [1].
Reference:
[1]. Scott CW, Briner CS, Wilkins DE, et al. Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis. J Pharmacol Exp Ther, 2003, 304(1): 433-40.

Molecular docking and CoMFA studies of thiazoloquin(az)olin(on)es as CD38 inhibitors: determination of inhibitory mechanism, pharmacophore interactions, and design of new inhibitors.[Pubmed:27577102]

J Biomol Struct Dyn. 2017 Jul;35(9):1890-1898.

In this research, molecular docking and 3D-QSAR studies were carried out on a series of 79 thiazoloquin(az)olin(on)es as CD38 inhibitors. Based on docking results, four interactions including hydrogen bonding with main chain of GLU-226 (H-M-GLU-226), Van der Waals interactions with side chain of TRP-125 (V-S-TRP-125), TRP-189 (V-S-TRP-189), and THR-221 (V-S-THR-221) were considered as pharmacological interactions. Active conformation of each ligand was extracted from docking studies and was used for carrying out 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) was performed on CD38 inhibitory activities of these compounds on human and mouse. We developed CoMFA models with five components as optimum models for both data-sets. For human data-set, a model with high predictive power was developed. R(2), RMSE, and F-test values for training set of this model were .94, .24, and 179.58, respectively, and R(2) and RMSE for its test set were .92 and .32, respectively. The q(2) and RMSE values for leave-one-out cross validation test on training set were .78 and .46, respectively, that demonstrate created model is robust. Based on extracted steric and electrostatic contour maps for this model, three inhibitors with pIC50 larger than 8.85 were designed.

Helicobacter pylori VacA, acting through receptor protein tyrosine phosphatase alpha, is crucial for CagA phosphorylation in human duodenum carcinoma cell line AZ-521.[Pubmed:27935824]

Dis Model Mech. 2016 Dec 1;9(12):1473-1481.

Helicobacter pylori, a major cause of gastroduodenal diseases, produces vacuolating cytotoxin (VacA) and cytotoxin-associated gene A (CagA), which seem to be involved in virulence. VacA exhibits pleiotropic actions in gastroduodenal disorders via its specific receptors. Recently, we found that VacA induced the phosphorylation of cellular Src kinase (Src) at Tyr418 in AZ-521 cells. Silencing of receptor protein tyrosine phosphatase (RPTP)alpha, a VacA receptor, reduced VacA-induced Src phosphorylation. Src is responsible for tyrosine phosphorylation of CagA at its Glu-Pro-Ile-Tyr-Ala (EPIYA) variant C (EPIYA-C) motif in Helicobacter pylori-infected gastric epithelial cells, resulting in binding of CagA to SHP-2 phosphatase. Challenging AZ-521 cells with wild-type H. pylori induced phosphorylation of CagA, but this did not occur when challenged with a vacA gene-disrupted mutant strain. CagA phosphorylation was observed in cells infected with a vacA gene-disrupted mutant strain after addition of purified VacA, suggesting that VacA is required for H. pylori-induced CagA phosphorylation. Following siRNA-mediated RPTPalpha knockdown in AZ-521 cells, infection with wild-type H. pylori and treatment with VacA did not induce CagA phosphorylation. Taken together, these results support our conclusion that VacA mediates CagA phosphorylation through RPTPalpha in AZ-521 cells. These data indicate the possibility that Src phosphorylation induced by VacA is mediated through RPTPalpha, resulting in activation of Src, leading to CagA phosphorylation at Tyr972 in AZ-521 cells.

Sequence of Reston Virus Isolate AZ-1435, an Ebolavirus Isolate Obtained during the 1989-1990 Reston Virus Epizootic in the United States.[Pubmed:28082493]

Genome Announc. 2017 Jan 12;5(2). pii: 5/2/e01448-16.

Reston virus (RESTV) was discovered in 1989-1990 during three connected epizootics of highly lethal viral hemorrhagic fever among captive macaques in primate housing facilities in the United States and Philippines. Currently, only one RESTV isolate from that outbreak (named Pennsylvania) has been sequenced. Here, we report the sequence of a second isolate, Reston virus/M.fascicularis-tc/USA/1990/Philippines89-AZ1435.

Synchronicity of influenza activity within Phoenix, AZ during the 2015-2016 seasonal epidemic.[Pubmed:28143437]

BMC Infect Dis. 2017 Jan 31;17(1):109.

BACKGROUND: Variability in the timing of influenza epidemics has been observed across global and regional scales, but this variability has not been studied extensively at finer spatial scales. As such, the aim of this study was to test whether influenza cases were synchronized across sites and/or age-groups within a major city. METHODS: We used influenza cases identified by rapid influenza tests from a network of clinics across Phoenix, AZ during the 2015-2016 influenza A season. We used a combination of KS tests and a bootstrapping approach to evaluate whether the temporal distribution of cases varied by site and/or age group. RESULTS: Our analysis indicates that the timing of influenza cases during the 2015-2016 seasonal influenza epidemic were generally synchronized across sites and age groups. That said, we did observe some statistically significant differences in the timing of cases across some sites, and by site and age group. We found no evidence that influenza activity consistently begins or peaks earlier in children than in adults. CONCLUSIONS: To our knowledge, this is the first study to investigate differences in the intra-urban timing of influenza using influenza-specific case data. We were able to show evidence that influenza cases are not entirely synchronized across an urban area, but the differences we observed were relatively minor. It is important to understand the geographic scale at which influenza is synchronized in order to gain a better understanding of local transmission dynamics, and to determine the appropriate geographic scale that influenza surveillance data should be aggregated for prediction and warning systems.

Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis.[Pubmed:12490620]

J Pharmacol Exp Ther. 2003 Jan;304(1):433-40.

Caspase-3 is an intracellular cysteine protease, activated as part of the apoptotic response to cell injury. Its interest as a therapeutic target has led many to pursue the development of inhibitors. To date, only one series of nonpeptidic inhibitors have been described, and these have limited selectivity within the caspase family. Here we report the properties of a series of anilinoquinazolines (AQZs) as potent small molecule inhibitors of caspase-3. The AQZs inhibit human caspase-3 with Ki values in the 90 to 800 nM range. A subset of AQZs are equipotent against caspase-6, although most lack activity against this isoform and caspase-1, -2, -7, and -8. The AQZs inhibit endogenous caspase-3 activity toward a cell permeable, exogenously added substrate in staurosporine-treated SH-SY5Y cells. The AQZs reduce biochemical and cellular features of apoptosis that are thought to be a consequence of caspase-3 activation including DNA fragmentation, TUNEL staining, and the various morphological features that define the terminal stages of apoptotic cell death. Moreover, the AQZs also inhibit apoptosis induced by nerve growth factor withdrawal from differentiated PC12 cells. Thus, the AQZs represent a new and structurally novel class of inhibitors, some of which selectively inhibit caspase-3 and will thereby allow evaluation of the role of caspase-3 activity in various cellular models of apoptosis.