Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action.

摘要: Successful drug discovery requires accurate decision making in order to advance the best candidates from initial lead identification final approval. Chemogenomics, use of genomic tools pharmacology and toxicology, offers a promising enhancement traditional methods target identification/validation, identification, efficacy evaluation, toxicity assessment. To realize value chemogenomics information, contextual database is needed relate physiological outcomes induced by diverse compounds gene expression patterns measured same animals. Massively parallel characterization coupled with assessments provides additional, important mechanistic therefore means increase accuracy critical decisions. A large-scale developed vivo treated rats context supporting data enhance accelerate interpretation mechanisms chemicals drugs. date, approximately 600 different compounds, including more than 400 FDA approved drugs, 60 drugs Europe Japan, 25 withdrawn 100 toxicants, have been profiled up 7 tissues (representing over 3200 drug-dose-time-tissue combinations). Accomplishing this task required evaluating improving number microarray protocols, 80 rigorous quality control steps. The utility pairing clinical pathology illustrated using three anti-neoplastic drugs: carmustine, methotrexate, thioguanine, which had similar effects on blood compartment, but hepatotoxicity. We will demonstrate that events monitored liver can be used predict pathological occurring tissue as well hematopoietic tissues.