Presents the Friday Keck Center Teleconference*
Using Mouse Genetics to Guide Drug Discovery
Brian P. Zambrowicz, Ph.D.,
Executive Vice President and Chief Scientific Officer
Lexicon Pharmaceuticals
4:00 pm Friday
Sept. 28th , 2007
(Refreshments at 3:45)
5.521 Levin Hall
Abstract: We have set up a large scale genetic screen using mouse knockouts to identify novel mechanisms for drug discovery. The latest estimates suggest that there are 20,448 protein-encoding genes in the human genome. We have focused on the subset of genes that encode proteins that are considered tractable for either small molecule or antibody-based drug discovery. This set of genes numbers about 5,000 and we have completed the knockout and phenotypic analysis of 4,200 of these genes. The screen is designed to identify potent and clean (mechanism-based) mechanisms for drug discovery. I will describe two drug discovery programs initiated based upon the mouse knockout data. The first is an antibody program targeting the Angptl4 protein. The knockout phenotype was a dramatic lowering of triglycerides and cholesterol with a lymphatic pathology when animals were fed a high fat diet. To address the question of whether there was a therapeutic window for target inhibition, we produced a hypomorphic allele that exhibited about 17% of normal enzymatic activity. Both examples demonstrate the utility of mouse genetics to guide drug discovery and predict potential mechanism-based toxicity. ( http://www.lexpharma.com )
