Preclinical pharmacology and pharmacokinetics of CERC-301, a GluN2B-selective N-methyl-D-aspartate receptor antagonist.

The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.

Larazotide acetate regulates epithelial tight junctions in vitro and in vivo.

Tight junctions (TJs) control paracellular permeability and apical-basolateral polarity of epithelial cells, and can be regulated by exogenous and endogenous stimuli. Dysregulated permeability is associated with pathological conditions, such as celiac disease and inflammatory bowel disease. Herein we studied the mechanism by which larazotide acetate, an 8-mer peptide and TJ regulator, inhibits the cellular changes elicited by gliadin fragments, AT-1002, and cytokines.

Mechanism of action of ZOT-derived peptide AT-1002, a tight junction regulator and absorption enhancer.

Tight junctions (TJs) are intercellular structures that control paracellular permeability and epithelial polarity. It is now accepted that TJs are highly dynamic structures that are regulated in response to exogenous and endogenous stimuli. Here, we provide details on the mechanism of action of AT-1002, the active domain of Vibrio cholerae's second toxin, zonula occludens toxin (ZOT).

Expression levels of protein kinase C-alpha in non-small-cell lung cancer.

Current treatments of non-small-cell lung cancer (NSCLC) are inadequate and new therapies are being developed that target specific cellular signaling proteins associated with tumor growth. One potential target is protein kinase C (PKC)-alpha, a signaling molecule with an important role in cell regulation and proliferation. The present study examines the expression levels of PKC-alpha in NSCLC to better understand the distribution of PKC-alpha in NSCLC.

Protein kinase C alpha expression in breast and ovarian cancer.

In recent years research has focused on the development of specific, targeted drugs to treat cancer. One approach has been to block intracellular signaling proteins, such as protein kinase C alpha (PKC-alpha). To help support the rationale for clinical studies of a PKC-alpha-targeted therapy in breast and ovarian cancers, we reviewed publications studying PKC-alpha expression in these tumors.

The role of protein kinase C-alpha in malignancies of the nervous system and implications for the clinical development of the specific PKC-alpha inhibitor aprinocarsen (Review).

Antisense oligonucleotide (ASO) technology offers a novel approach for the development of anti-cancer drugs. For example, the ASO aprinocarsen has been developed to specifically inhibit the intracellular signal transduction protein, protein kinase C-alpha (PKC-alpha). The clinical development of such specific or "new targeted" agents in cancer requires a comprehensive understanding of the target protein.