gdc-0449 and Alzheimer-Disease

Given the costly and time consuming process and high attrition rates in drug discovery and development, drug repositioning or drug repurposing is considered as a viable strategy both to replenish the drying out drug pipelines and to surmount the innovation gap. Although there is a growing recognition that mechanistic relationships from molecular to systems level should be integrated into drug discovery paradigms, relatively few studies have integrated information about heterogeneous networks into computational drug-repositioning candidate discovery platforms.. Using known disease-gene and drug-target relationships from the KEGG database, we built a weighted disease and drug heterogeneous network. The nodes represent drugs or diseases while the edges represent shared gene, biological process, pathway, phenotype or a combination of these features. We clustered this weighted network to identify modules and then assembled all possible drug-disease pairs (putative drug repositioning candidates) from these modules. We validated our predictions by testing their robustness and evaluated them by their overlap with drug indications that were either reported in published literature or investigated in clinical trials.. Previous computational approaches for drug repositioning focused either on drug-drug and disease-disease similarity approaches whereas we have taken a more holistic approach by considering drug-disease relationships also. Further, we considered not only gene but also other features to build the disease drug networks. Despite the relative simplicity of our approach, based on the robustness analyses and the overlap of some of our predictions with drug indications that are under investigation, we believe our approach could complement the current computational approaches for drug repositioning candidate discovery.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Anilides; Basal Cell Nevus Syndrome; Cluster Analysis; Computational Biology; Computer Graphics; Databases, Factual; Drug Repositioning; Hidradenitis Suppurativa; Humans; Phenotype; Protease Inhibitors; Pyridines

CHI's 17th International Tri-Conference on Molecular Medicine, held in San Francisco, included topics covering new developments in the field of medicinal chemistry. This conference report highlights selected presentations on fragment-based drug discovery, quantum mechanical energy decomposition for the analysis of SARs, medicinal chemistry strategies and the role of imaging in drug discovery. Investigational drugs discussed include MLN-4924 (Millennium Pharmaceuticals Inc), GDC-0449 (Chugai Pharmaceutical Co Ltd/Curis Inc/F Hoffmann-La Roche Ltd/Genentech Inc/NCI), RDEA-119 (Ardea Biosciences Inc/Bayer HealthCare AG) and tafamidis (Fx-1006A; FoldRx Pharmaceuticals Inc).

Topics: Alzheimer Disease; Amyloidosis; Anilides; Animals; Benzoxazoles; Chemistry, Pharmaceutical; Drug Discovery; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; HSP90 Heat-Shock Proteins; Humans; Macrocyclic Compounds; Neoplasms; Pharmacokinetics; Positron-Emission Tomography; Pyridines; Quantum Theory; Receptors, Immunologic; Receptors, Prostaglandin; Structure-Activity Relationship