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1.
PLoS One ; 13(10): e0204648, 2018.
Article in English | MEDLINE | ID: mdl-30300381

ABSTRACT

Different computational approaches are employed to efficiently identify novel repositioning possibilities utilizing different sources of information and algorithms. It is critical to propose high-valued candidate-repositioning possibilities before conducting lengthy in vivo validation studies that consume significant resources. Here we report a novel multi-methodological approach to identify opportunities for drug repositioning. We performed analyses of real-world data (RWD) acquired from the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) and the claims database maintained by the Japan Medical Data Center (JMDC). These analyses were followed by cross-validation through bioinformatics analyses of gene expression data. Inverse associations revealed using disproportionality analysis (DPA) and sequence symmetry analysis (SSA) were used to detect potential drug-repositioning signals. To evaluate the validity of the approach, we conducted a feasibility study to identify marketed drugs with the potential for treating inflammatory bowel disease (IBD). Primary analyses of the FAERS and JMDC claims databases identified psycholeptics such as haloperidol, diazepam, and hydroxyzine as candidates that may improve the treatment of IBD. To further investigate the mechanistic relevance between hit compounds and disease pathology, we conducted bioinformatics analyses of the associations of the gene expression profiles of these compounds with disease. We identified common biological features among genes differentially expressed with or without compound treatment as well as disease-perturbation data available from open sources, which strengthened the mechanistic rationale of our initial findings. We further identified pathways such as cytokine signaling that are influenced by these drugs. These pathways are relevant to pathologies and can serve as alternative targets of therapy. Integrative analysis of RWD such as those available from adverse-event databases, claims databases, and transcriptome analyses represent an effective approach that adds value to efficiently identifying potential novel therapeutic opportunities.


Subject(s)
Pharmaceutical Preparations/administration & dosage , Adult , Adverse Drug Reaction Reporting Systems , Algorithms , Child, Preschool , Computational Biology/methods , Cytokines/metabolism , Databases, Factual , Drug Repositioning/methods , Drug-Related Side Effects and Adverse Reactions/prevention & control , Gene Expression/drug effects , Humans , Japan , Middle Aged , Signal Transduction/drug effects , United States , United States Food and Drug Administration , Young Adult
2.
Enzymes ; 33 Pt A: 213-48, 2013.
Article in English | MEDLINE | ID: mdl-25033807

ABSTRACT

MCP compounds were developed with the idea to inhibit RAS/RAF interaction. They were identified by carrying out high-throughput screens of chemical compounds for their ability to inhibit RAS/RAF interaction in the yeast two-hybrid assay. A number of compounds including MCP1, MCP53, and MCP110 were identified as active compounds. Their inhibition of the RAS signaling was demonstrated by examining RAF and MEK activities, phosphorylation of ERK as well as characterizing their effects on events downstream of RAF. Direct evidence for the inhibition of RAS/RAF interaction was obtained by carrying out co-IP experiments. MCP compounds inhibit proliferation of a wide range of human cancer cell lines. Combination studies with other drugs showed that MCP compounds synergize with MAPK pathway inhibitors as well as with microtubule-targeting chemotherapeutics. In particular, a strong synergy with paclitaxel was observed. Efficacy to inhibit tumor formation was demonstrated using mouse xenograft models. Combination of MCP110 and paclitaxel was particularly effective in inhibiting tumor growth in a mouse xenograft model of colorectal carcinoma.


Subject(s)
Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Proto-Oncogene Proteins c-raf/metabolism , ras Proteins/antagonists & inhibitors , ras Proteins/metabolism , Animals , Humans , Mice , Two-Hybrid System Techniques
3.
J Med Chem ; 55(7): 3452-78, 2012 Apr 12.
Article in English | MEDLINE | ID: mdl-22376051

ABSTRACT

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Thiazoles/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzamides/pharmacokinetics , Benzamides/pharmacology , Benzoates/chemical synthesis , Benzoates/pharmacokinetics , Benzoates/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Models, Molecular , Molecular Structure , Phosphorylation , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Xenograft Model Antitumor Assays
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