Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 1

High-Throughput in vivo Assessment of Small Molecule Efficacy and Safety

Randall Peterson, Ph.D.
Assistant Professor, Massachusetts General Hospital, Harvard Medical School
Associate Member, Broad Institute of MIT and Harvard

Recent advances in synthetic chemistry, robotics, and assay development have fueled rapid expansion of chemical biology into many areas of biomedical inquiry. For biological processes that can be distilled down to an in vitro reaction or simple cellular phenotype, high-throughput screening can often identify small molecule modifiers that disrupt the process. These chemical probes have proven to be invaluable tools for fundamental biomedical research and for treating disease.

Unfortunately, much of biology cannot be reduced to a simple in vitro assay. As examples, many aspects of normal embryogenesis, disease pathology, and small molecule toxicity involve complex interplay between various organs and tissue types. These organismal processes are best studied in vivo, and consequently have not been amenable to large-scale chemical biology. We have developed methodologies that enable a chemical biology approach to be applied to organismal processes in vivo. By exploiting the small size, optical transparency, and fecundity of the zebrafish, the approach has enabled us to identify potent, specific small molecule modifiers of many aspects of vertebrate development, to discover novel compounds that suppress disease phenotypes, and to test small molecule toxicity in rapid throughput. We are currently exploring the developmental pathways involved in myocardial infarction recovery, acute myeloid leukemia, and anemia and testing whether our small molecule modifiers will also be helpful for studying or treating these diseases.

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