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Summary: Stuart Schreiber's lab has developed systematic ways to use small molecules (precursors to therapeutic drugs that are used as bioprobes) to explore cell circuitry and disease biology. His lab is also known for having helped develop the area of chemical biology. Using his chemical approach, he has discovered principles that underlie information transfer and storage in cells.

My lab performs research in chemical biology, which is a field focused on small molecules and their roles in the life sciences. The famous central dogma of biology draws attention to macromolecules (DNA, RNA, proteins), yet life would not be possible without small molecules. Small molecules are key to understanding memory and cognition, signaling and sensing, and the origins of life. They also function as powerful probes of life processes, and as medicines for the treatment of disease. Connections exist between each of the three key macromolecules of life and small molecules; examples include DNA-templated small-molecule synthesis, small-molecule riboswitches, and small-molecule modulators of protein function.

Two of the missions of chemical biology are (1) to complete the inventory of all natural small molecules and identify a small-molecule modulator for each individual function of all macromolecules, and (2) to probe cell circuitry and disease biology in order to bridge basic and clinical research. My research addresses these goals by focusing on small-molecule synthesis, small-molecule screening, and the development of a public data repository and data analysis environment for small molecules and assay measurements (ChemBank).

	Figure 1: Signatures of cell states corresponding to tumorigenesis... Figure 2: Schematic of ChemBank and analysis tools...

My lab's research has led to insights into signal transmission from the membrane to the nucleus in cells, for example, the calcium-calcineurin-NFAT (immunophilin-drug complexes target calcineurin, in 1991) and nutrient response-signaling networks (discovery of mTOR in 1994). Our research on the role of chromatin in gene regulation (beginning with the cloning, purification, and characterization of histone deacetylases in 1996) helped define the network motifs that underlie chromatin as a signaling network, rather than a code based on combinatorial histone marks. We have discovered small-molecule probes that have illuminated the cellular functions of numerous proteins, including transcription factors, motor proteins named kinesins, and enzymes that regulate protein homeostasis, a key process in cancers such as multiple myeloma.

Trainees in my group and I develop and use diversity-oriented synthesis (DOS) to gain access to stereochemically and skeletally diverse small molecules. We use many screening techniques—both to identify the small molecules that modulate protein function in cells and to create signatures of small molecules and cell states—that enable us to explore chemical space and to characterize cell circuitry (Figure 1). We also use information science to create analysis tools for small molecules and small-molecule screens. These tools are key elements of ChemBank, our Internet-accessible database (Figure 2).

Last updated: May 6, 2008