Establishing Drosophila Tools for Pathway Mapping and Target Identification

DESCRIPTION (provided by applicant): The pharmaceutical industry is under growing scrutiny due to the high failure rate in the clinic and the exorbitant cost of research resulting in expensive medications and growing healthcare expenditures. Increased research and development budgets have had little effect on drugs entering the market place, so clearly a new paradigm for drug discovery is needed to face the healthcare challenges of the 21st century. MEDROS has a long term goal of impacting the pharmaceutical industry by putting better drugs into the clinic through the development of a different approach to drug discovery. MEDROS was founded on a proprietary platform that uses fruit fly models of human diseases to search for novel medicines. An important proof-of-concept for our technology came from our academic collaborators who used this approach to demonstrate activity of a drug now in Phase III clinical trials for Medullary Thyroid Carcinoma. The technology uses high-throughput whole organism drug screening to quickly assess chemical compound efficacy, potency, compound stability, safety, and bioavailability all in one experiment. To further leverage the advantages of Drosophila drug discovery, the aims in this proposal are designed to develop Drosophila as a tool for molecular pathway mapping. This proposal is designed to address the one important liability common to all phenotypic screens, the fact that mechanism of action for hits emerging from the screen is typically not known. MEDROS is uniquely suited to tackle this problem by combining the power of Drosophila genetics with genomic and chemical biology tools. In this Proposal, two in situ mapping approaches will be developed as the starting point for this process. First, we will assess and validate the use of classical genetic modifier screening as a tool for identifying signalling pathways altered by individual chemical compounds. Second, we will use microarray analysis to generate 'fingerprint' expression patterns useful for determining pathways altered by compounds. Successful deployment of a process to easily and accurately define mechanism of action will provide an important extension to our approach, and provide avenues for potential strategic partnerships. PUBLIC HEALTH RELEVANCE: Drug discovery faces ever-increasing difficulties as the demand for sophisticated, effective therapeutics grows. MEDROS has developed a whole animal drug screening method to address this need by emphasizing whole animal compound screening. This proposal further uses the fruit fly D. melanogaster to identify the factors targeted by new generation candidate therapeutics.