Discovery of a novel class of AKT pleckstrin homology domain inhibitors.

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain.

Actin microfilament aggregation induced by withaferin A is mediated by annexin II.

The actin cytoskeleton supports diverse cellular processes such as endocytosis, oriented growth, adhesion and migration. The dynamic nature of the cytoskeleton, however, has made it difficult to define the roles of the many accessory molecules that modulate actin organization, especially the multifunctional adapter protein annexin II. We now report that the compound withaferin A (1) can alter cytoskeletal architecture in a previously unknown manner by covalently binding annexin II and stimulating its basal F-actin cross-linking activity.

Amino acid changes in Drosophila alphaPS2betaPS integrins that affect ligand affinity.

We developed a ligand-mimetic antibody Fab fragment specific for Drosophila alphaPS2betaPS integrins to probe the ligand binding affinities of these invertebrate receptors. TWOW-1 was constructed by inserting a fragment of the extracellular matrix protein Tiggrin into the H-CDR3 of the alphavbeta3 ligand-mimetic antibody WOW-1. The specificity of alphaPS2betaPS binding to TWOW-1 was demonstrated by numerous tests used for other integrin-ligand interactions.

Strategies for targeting the multidrug resistance-1 (MDR1)/P-gp transporter in human malignancies.

ATP-binding cassette (ABC) transporters are a super family of channel proteins that include multi-drug resistance 1 (MDR1/P-gp) and multi-drug resistance related proteins (MRPs) whose functions include the efflux of ions, nutrients, lipids, amino acids, peptides, proteins and drugs. The three-dimensional structures of bacterial and human ABC transporters demonstrate that these proteins are ATP-dependent molecular machines that scan the inner membrane leaflet for lipids/drugs and flip them to the outer membrane leaflet. In many human cancers, the level of expression of MDR1 is an important independent prognostic factor that determines response to combination chemotherapy.

A conserved glutamate residue in transmembrane helix 10 influences substrate specificity of rabbit OCT2 (SLC22A2).

OCT1 and OCT2 are involved in renal secretion of cationic drugs. Although they have similar selectivity for some substrates (e.g.