University of North Carolina's experience with state medical assistance teams.

Events in the last several years have shown a clear need for better preparation regarding disaster management. In an effort to improve this preparation, North Carolina implemented state medical assistant teams to provide alternative care facilities, decontamination facilities, and shelter assistance during times of disaster. This article explores these teams from the perspective of the University of North Carolina, which serves as a lead agency for one of these teams.

Synthesis and evaluation of indazole based analog sensitive Akt inhibitors.

The kinase Akt is a key signaling node in regulating cellular growth and survival. It is implicated in cancer by mutation and its role in the downstream transmission of aberrant PI3K signaling. For these reasons, Akt has become an increasingly important target of drug development efforts and several inhibitors are now reaching clinical trials.

Discovery of dual inhibitors of the immune cell PI3Ks p110delta and p110gamma: a prototype for new anti-inflammatory drugs.

PI3Kdelta and PI3Kgamma regulate immune cell signaling, while the related PI3Kalpha and PI3Kbeta regulate cell survival and metabolism. Selective inhibitors of PI3Kdelta/gamma represent a potential class of anti-inflammatory agents lacking the antiproliferative effects associated with PI3Kalpha/beta inhibition. Here we report the discovery of PI3Kdelta/gamma inhibitors that display up to 1000-fold selectivity over PI3Kalpha/beta and evaluate these compounds in a high-content inflammation assay using mixtures of primary human cells.

Inhibitor hijacking of Akt activation.

The kinase Akt plays a central role as a regulator of multiple growth factor input signals, thus making it an attractive anticancer drug target. A-443654 is an ATP-competitive Akt inhibitor. Unexpectedly, treatment of cells with A-443654 causes paradoxical hyperphosphorylation of Akt at its two regulatory sites (Thr308 and Ser473).

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets.

A fragment-based approach for the discovery of isoform-specific p38alpha inhibitors.

In this study, we describe a novel approach for lead discovery against protein kinases, pharmacophore by interligand nuclear Overhauser effect (ILOE), in which a pair of ligands that bind to adjacent pockets on the target surface is identified by the detection of protein-mediated ILOEs. We demonstrate that a pharmacophore-based search guided by experimental binding data of weakly interacting fragments can be rapidly and efficiently used to identify (or synthesize) high-affinity, selective ligands. Targeting the inactive state of protein kinases represents a promising approach to achieve selectivity and cellular efficacy.

Overcoming compound interference in fluorescence polarization-based kinase assays using far-red tracers.

Kinase-mediated phosphorylation of proteins is critical to the regulation of many biological processes, including cell growth, apoptosis, and differentiation. Because of the central role that kinases play in processes that can lead to disease states, the targeting of kinases with small-molecule inhibitors is a validated strategy for therapeutic intervention. Classic methods for assaying kinases include nonhomogenous enzyme-linked immunosorbent assays or scintillation-based formats using [gamma-(32)P]ATP.