Tag: drug discovery
Converting Pancreatic α-Cells to β-Like-Cells
There are four main cell types in the islets of Langerhans in the pancreas; α-cells which secrete glucagon, β-cells which secrete insulin, δ-cells which secrete somatostatin, and PP cells which secrete pancreatic polypeptide. Type I diabetes is an autoimmune disease in which the insulin-producing β-cells are destroyed and could potentially be treated by the creation of new β-cells, either from stem or stem-like cells or by conversion of another mature cell type. It has recently been shown that the transcription factor, Pax4, induces transdifferentiation of pancreatic α-cells into β-cells in adult mice and a team led by researchers at the Broad Institute of Harvard and MIT has now shown that a similar effect can be achieved with a small molecule.
Follow-up studies suggested that upregulation of insulin expression potentially involved inhibition of multiple members of the RSK family of protein kinases, but more experiments are needed to fully elucidate the mechanism of action of BRD7389. The study demonstrates, however, that a small molecule can induce insulin expression in α-cells and suggests that such a strategy could be used to increase β-cell mass by transdifferentiation in vivo. The team now want to identify other small molecules that could be used to enhance the effects of BRD7389, and boost insulin production in people with type I diabetes.
The study is published in PNAS.
Potential New Drugs for Epilepsy
The study is published in the Proceedings of the National Academy of Sciences.
PPARγ– A New Twist in the Tale
Researchers at the Scripps Research Institute and the Dana-Farber Cancer Institute at Harvard University have now shown that cyclin-dependent kinase 5 (Cdk5) in adipose tissue is activated in obese mice fed a high-fat diet, resulting in phosphorylation of PPARγ. This has no effect on the adipogenic capacity of PPARγ but does alter the expression of a large number of obesity-related genes, including a reduction in expression of the insulin-sensitizing adipokine, adiponectin. Phosphorylation of PPARγ by Cdk5 was blocked both in vitro and in vivo by the full agonist, rosiglitazone, and by the partial agonist, MRL-24, leading to increased adiponectin production. The anti-diabetic effect of rosiglitazone in obese patients was also found to be closely associated with inhibition of PPARγ phosphorylation, suggesting that this may be a mechanism of insulin resistance. The authors of the study, which is published in the journal Nature, suggest that drugs that inhibit PPARγ phosphorylation by Cdk5, without necessarily activating the receptor, may provide an improved generation of anti-diabetic drugs.
Study Finds Compounds that Boost Neurogenesis: Possible moa for Dimebon
An in vivo screen of 1000 small molecules in adult mice identified eight compounds that were able to enhance neuron formation in the subgranular zone of the hippocampal dentate gyrus. One of the compounds, P7C3, was selected for further study on the basis of favourable ADME predictions. Daily administration of P7C3 to aged rats for 7 days was shown to enhance hippocampal neurogenesis relative to control animals and, after 2 months, treated rats performed significantly better in the Morris water maze test which provides a measure of learning and memory.
P7C3 exerts its proneurogenic effects by protecting newborn neurons from apoptosis and the team next compared the activity of P7C3 with that of Dimebon, which is also believed to have anti-apoptotic activity. Dimebon was found to be proneurogenic in vivo, albeit at levels 10-30 times higher than P7C3, raising the possibility that the two compounds may share a common mechanistic pathway. Although this idea can only be rigorously tested after identification of the molecular target(s), the study raises the hope that more potent analogues of Dimebon with improved clinical efficacy could be identified and also provides appropriate assays.
The study is published in the journal Cell.
Breathe Easy
The, lung-on-a-chip has the potential to model the effects of environmental toxins, the inflammatory response to inhaled pathogens and the effectiveness of new drugs. Because the chip is transparent, responses can be captured in real time using high-resolution fluorescence microscopy. When E.Coli bacteria were introduced into the air on the ‘lung’ side of the chip, white blood cells on the ‘blood’ side of the chip migrated through the porous membrane into the air chamber to destroy the bacteria. ‘Breathing’ was found to enhance absorption of nanoparticles, some of which induced an inflammatory response and overproduction of free radicals by the lung cells.
The team are now exploring whether the system can mimic gas exchange between alveolar cells and the bloodstream and believe that the device provides proof-of-principle for the concept that organs-on-chips could replace many animal studies in the future.
The study is published in the journal Science.
Oestrogen – Better Out than In for Cardiovascular Health
The increased cancer risk is linked to oestrogen’s action at nuclear receptors but researchers at UT Southwestern Medical Center have now found that a subpopulation of oestrogen receptors outside the cell nucleus mediate the beneficial cardiovascular effects. The extra-nuclear receptors in endothelial cells are important for blood vessel maintenance and repair and also regulate production of nitric oxide which has a number of beneficial cardiovascular effects. The team have found that an oestrogen-macromolecule complex which is excluded from the nucleus is highly effective in stimulating the extra-nuclear receptors. Similar dendrimer conjugates have been successfully used as drug delivery device in animal models and the oestrogen complex was shown to provide cardiovascular protection in high cholesterol ovariectomized female mice without stimulating growth of breast or uterine cancer. The team believe that such oestrogen-macromolecule complexes could provide cardiovascular protection for both men and women and are creating molecules that may be suitable for use in humans.
The study is published in the Journal of Clinical Investigation.
For cells, too, 2-D is not the same as 3-D
Cell culture experiments to screen for compounds that can inhibit cell migration – and potentially metastasis of cancer cells – are typically carried out in a 2-D environment, but researchers at Johns Hopkins University and the University of Washington suggest that results from such experiments may be, at best, misleading. The team has shown that the way in which cells move in a 3-D environment, such as the human body, is different both qualitatively and quantitatively from the way they move in a 2-D environment such as a culture dish. When cells are grown in 2-D, they develop broad fan-shaped protrusions called lamella along their leading edge which help them to move forward. Macromolecular assemblies known as focal adhesions which can last for up to several minutes are also formed. These focal adhesions mediate cell signalling, force transduction and adhesion. In 3-D, the cells take on a more spindle-like appearance, with two pointed protrusions at opposite ends and focal adhesions – if they form at all – are so small and short-lived that they cannot be resolved by microscopy. The authors suggest that the shape and movement of cells in 2-D culture experiments are artifacts of the environment and could produce misleading results in studies to test the effects of drugs on cell motility. This may explain why positive results from cell culture experiments do not always translate into efficacy in animal models.
Even in cell culture systems designed to more closely mimic a 3-D environment, the cells may be only partially embedded in a matrix and produce misleading results. Using live-cell microscopy, the team showed that, when cells are fully embedded in a 3-D matrix, focal adhesion proteins do not form aggregates, but are distributed throughout the cytoplasm. The focal adhesion proteins still modulate cell motility, but not in the same way as in a 2-D environment. Because loss of adhesion and increased motility are hallmarks of cancer cells, it is important to understand cell motility under physiological conditions and to use culture techniques that most closely mimic this.
The study is published in Nature Cell Biology.
NSAIDs and Cancer – Another Piece of the Puzzle
The use of NSAIDs to reduce the incidence of cancer has been limited by the risk of major cardiovascular events and the Sanford-Burnham have identified an analogue of sulindac sulfide, K-80003 which has improved affinity for RXRα but lacks significant COX-2 inhibitory activity. K-80003 inhibited the growth of cancer cells in vitro and in animals and would be expected to have reduced COX-2-associated side effects.
The study is published in the journal Cancer Cell.
Targeting Influenza A Nucleoprotein
Although the recent sporadic outbreaks of influenza A virus H5N1 and of a new variant of H1N1 in 2009 were less serious than initially feared, public health responses gave an indication of the potential for pandemic influenza A to wreak havoc amongst human populations. Timely development of vaccines should help to contain future outbreaks, but effective antiviral medicines will also be needed. Circulating strains of influenza A virus with resistance to existing neuraminidase inhibitors have already been discovered, and new molecular targets would provide additional protection in the event of a fresh outbreak.

The study, which is published in Nature Biotechnology, shows that the nucleoprotein is a viable drug target and could lead to the development of new treatments to control the impact of future influenza A outbreaks. Potential binding sites for nucleozin on the influenza nucleoprotein were also predicted using molecular docking models.