title: Morphogenics as a tool for target discovery and drug development.
abstract: Mutations in DNA mismatch repair (MMR) genes lead to genetically hypermutable cells. Germline mutations in MMR genes in man have been linked to the genetic predisposition to hereditary nonpolyposis colon cancer and a number of other inherited and sporadic malignancies. The ability to modulate the MMR process (referred to as morphogenics) in model systems offers a powerful tool for generating functional diversity in cells and multicellular organisms via the perpetual genomewide accumulation of randomized point and slippage mutation(s). Morphogenics is a platform process that employs a dominant negative MMR gene to create genetic diversity within defined cellular systems and results in a wide range of phenotypes, thus enabling the development and improvement of pharmaceutical products and the discovery of new pharmaceutical targets. Libraries of morphogenics-derived siblings are generated through random mutagenesis from naturally occurring DNA polymerase-induced mutations that occur during DNA replication. Morphogenic cells are screened in high-throughput assays to identify subclones with desired phenotypes for pathway discovery and/or product development. Morphogenics has been successfully applied to a wide range of hosts, including mammalian cells, transgenic mice, plants, yeast, and bacteria. Manipulation of these systems via morphogenics has led to the discovery of novel disease-associated phenotypes in targeted model systems. Moreover, morphogenics has been successfully applied to antibody-producing cell lines to yield subclones producing antibodies with enhanced binding affinities for therapeutic use, as well as to derive subclones with enhanced titers that are suitable for scaleable manufacturing. The selective manipulation of the MMR process via morphogenics is a platform technology that offers many advantages for the discovery of druggable targets, as well as for the development of novel pharmaceutical products.
authors.affiliation: Morphotek Inc., Exton, PA 19342, USA. nicolaides@morphotek.com
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Nicolaides
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Ebel
authors.forename: Brad
authors.initials: B
authors.lastname: Kline
authors.forename: Qimin
authors.initials: Q
authors.lastname: Chao
authors.forename: Eric
authors.initials: E
authors.lastname: Routhier
authors.forename: Philip M
authors.initials: PM
authors.lastname: Sass
authors.forename: Luigi
authors.initials: L
authors.lastname: Grasso
mesh_terms: D020137:Base Pair Mismatch; D002460:Cell Line; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004261:DNA Replication; D015195:Drug Design; D018095:Germ-Line Mutation; D006801:Humans; D008957:Models, Genetic; D000070956:MutL Proteins; D016296:Mutagenesis; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism
chemical_list: C500929:MutLalpha protein, human; D009363:Neoplasm Proteins; D000070956:MutL Proteins; D045643:DNA Repair Enzymes