We propose to create an Interdisciplinary Research Consortium (IRC) that will transform the process of drugdiscovery by integrating novel approaches from genomics, chemistry, imaging and computational science.Our approach is to augment the now traditional approach of target-based screening so that drugs can bedeveloped for situations where evidence points not to a single protein, but rather to a biological processinvolving many proteins, or an alteration in the state of the cell. With this goal, we propose the pursue thefollowing hypotheses: 1) that live cell screens based on gene-expression signatures (GE-HTS) andquantitative high-throughput live cell imaging (LCI-HTS) can be developed as a primary route to discoveringnew drugs, and 2) that when combined with novel approaches from Component B (Discovery Pipeline) andComponent C (Target ID), these projects will support the discovery of potent and safe drugs with novelmechanisms of action.In order to test these hypotheses and drive the development of new approaches to drug development,Component D will apply the capabilities developed in Component B (Discovery Pipeline) and Component C(Target ID) to six demonstration projects in three areas: 1) well-credentialed genes and pathways that arehighly relevant to human disease, and yet to date have failed to yield successful drugs; 2) based onknowledge of effective drugs in the clinic, and 3) pathways newly identified in vivo by human genetics asplaying causal roles in poorly treated diseases.Each of the six demonstration projects will proceed through four stages: 1) development of cell-basedassays, 2) screening for small-molecule leads, 3) identification of the target and medicinal chemistry tooptimize the lead compounds, and 4) evaluating efficacy and toxicity using in vivo animal models of disease.In summary, driven by our evaluation of the limitations and opportunities offered by traditional and novelapproaches to drug development, and combining the interdisciplinary approaches described in Component B(Discovery Pipeline) and Component C (Target ID) with disease-specific expertise in each of these sixdemonstration projects, Component D aims to validate a new paradigm for drug discovery, and makesignificant headway in discovering new small molecules for the treatment of important human diseases.
Showing the most recent 10 out of 29 publications
