Undergraduate, graduate and postdoctoral trainees in the Schreiber laboratory over the past 25 plus years have developed systematic ways to explore biology using small molecules (precursors to therapeutic drugs that are used as bioprobes). They have also helped to develop the emerging area of chemical biology, especially through their work in diversity-oriented synthesis (DOS) and small-molecule screening. Using their chemical approach, they have discovered principles that underlie information transfer and storage in cells. For a more detailed account of past efforts read the archived Research Detail.

Key Discoveries

Several discoveries that emerged from research in this laboratory are highlighted here. These relate to both cell circuitry by signaling proteins calcineurin and mTOR and gene regulation by chromatin-modifying histone deacetylases. Together, they illustrate how chemical biology advances the use of small molecules for exploring biology and medicine.

Calcium-calcineurin-NFAT signaling pathway. Following their co-discovery of the FK506-binding protein FKBP12 in 1988, members of the Schreiber lab reported that the small molecules FK506 and cyclosporin inhibit the activity of the phosphatase calcineurin by forming the ternary complexes FKBP12-FK506-calcineurin and cyclophilin-cyclosporin-calcineurin. This work, together with work by researchers in the Gerald Crabtree lab at Stanford concerning the NFAT proteins, led to the elucidation of the calcium-calcineurin-NFAT signaling pathway. It was an early example of defining an entire cellular signaling pathway from the cell surface to the nucleus, analogous to that of the Ras-Raf-MAPK pathway elucidated the following year. In more recent years, the calcium-calcineurin-NFAT pathway has been found to play a critical role in immune function, heart development, and the acquisition of memory in the hippocampus.

Small-molecule dimerizers. The above studies also led the Schreiber and Crabtree labs to jointly develop in 1993 small-molecule dimerizers, which provide small-molecule activation over numerous signaling molecules and pathways (e.g., the Fas, insulin, TGFb and T cell receptors) through proximity effects. Researchers in these labs demonstrated that small molecules could be used to influence signaling pathways in an animal with temporal and spatial control. Dimerizer kits have been distributed to over 1,100 laboratories, and its promise in gene therapy has been highlighted by the stable (over eight years), small molecule-induced production of erythropoeitin (EPO) in a primate (ARIAD Gene Therapeutics).

mTOR and the nutrient response-signaling network. In 1994, members of the Schreiber lab discovered that the small molecule rapamycin simultaneously binds FKBP12 and mTOR (originally named FKBP12-rapamycin binding protein, FRAP). Using chemical genetic epistasis analysis, diversity-oriented synthesis (DOS), small-molecule microarrays, among others, the nutrient-response signaling network involving TOR proteins in yeast and mammalian cells has been illuminated. Small molecules such as uretupamine, SMIRS and SMERs (inhibitors and activators of autophagy) and rapamycin were shown to be particularly effective in revealing the ability of TOR proteins to receive multiple inputs and to process them appropriately towards multiple outputs (multi-channel processors). These studies are beginning to uncover the relationship of the nutrient signaling network to cancer.

HDACs and chromatin. In 1996 members of the Schreiber lab used the small molecules trapoxin and depudecin to characterize molecularly the histone deacetylases (HDACs). Prior to this work, the HDAC proteins had not been isolated despite attempts by others in the field who had been inspired by Allfrey's detection of the enzymatic activity in cell extracts over 30 years earlier. Co-incident with the HDAC discovery, David Allis and colleagues reported their discovery of the histone acetyltransferases (HATs). These two contributions catalyzed research in this area, eventually leading to the characterization of numerous histone-modifying enzymes, their resulting histone marks, and numerous proteins that bind to these marks. By taking a global approach to understanding chromatin function, Schreiber and Bernstein proposed a signaling network model of chromatin and compared it to an alternative view, the histone-code hypothesis presented by Strahl and Allis. The work of many researchers in this area has shined a bright light on chromatin as a key regulatory element central to epigenetics, rather than simply a structural element.

Key Developments

Modern methods of organic synthesis and new DOS strategies are being used to synthesize small molecules whose diversity results from alterations in their skeletons and stereochemistry, rather than their appendages, and whose ability to be optimized or modified is facilitated by the purposeful placement of chemically orthogonal chemical handles. A primary contribution by trainees in the Schreiber lab has been to develop conceptually new strategies for planning such syntheses.

These advances and new techniques for small-molecule screening, have resulted in a dramatic increase in the pace and impact of small-molecule-based discoveries. For example, in collaboration with members of the Schreiber and Tim Mitchison labs, cytoblot screening was used to discover monastrol the first small molecule inhibitor of mitosis that does not target tubulin. Monastrol was shown to inhibit kinesin-5, a kinesin motor protein, and was used to gain new insights into the functions of kinesin-5. This work led pharmaceutical company Merck, among others, to pursue anti-cancer drugs that target this protein. DOS and small-molecule screening in the Schreiber lab have yielded small-molecule probes of autophagy, histone and tubulin deacetylases, histone demethylases, transcription factors, cytoplasmic anchoring proteins, developmental signaling proteins (e.g., histacin, tubacin, haptamide, uretupamine, concentramide, and calmodulophilin), among many others. Tubacin, a specific inhibitor of the dynein adaptor protein HDAC6, was shown to synergize with Velcade in multiple myeloma and to kill Velcade-resistant multiple myeloma cell lines; analogs are now being used in preclinical studies aiming at developing a new therapy for this disease. (link to Screening at a glance video)Multidimensional screening was introduced in 2002 and has provided insights into tumorigenesis, cell polarity, and chemical space, among others. More than 150 laboratories from over 40 institutions have collaborated in an open data-sharing environment Schreiber developed at the Broad Institute Chemical Biology Program (formerly the Harvard ICCB), leading to many small-molecule probes and insights into biology.

ChemBank. To facilitate the open sharing of small-molecule-based insights, researchers associated with these activities pioneered the development of the small-molecule and assay-data repository and analysis environment named ChemBank, which was launched on the Internet in 2003. ChemBank makes accessible to the public (over 50,000 users from over 8,000 institutions in 154 countries) results and analyses involving over 2,000 small-molecule screens and 20 million assay (well) measurements. This has enabled cross-sectional analyses of small-molecule screens, a powerful method for understanding the effects of small molecules and for illuminating the circuitry that underlies cellular signaling.

Impact on human physiology and medicine. Over 100 published papers by trainees in the Schreiber lab have received 100 citations or more (h-index = 105), resulting in one of the top rankings among chemistry labs in terms of citations. In 2007, two new anti-cancer drugs that target proteins discovered in the Schreiber laboratory using the small-molecule approach were approved by the U.S. FDA: torisel (Wyeth; treatment of renal cell carcinoma), which targets mTOR (discovered in 1994) and vorinostat (Merck; treatment of cutaneous T-cell lymphoma), which targets HDACs (HDAC1 discovered in 1996). Chemical biology principles developed in the Schreiber lab have been extended to medicine additionally through the founding of biopharmaceutical companies, including Vertex Pharmaceuticals (1989), ARIAD Pharmaceuticals (1991) and Infinity Pharmaceuticals (2001), each of which has devised new therapeutic agents that are being tested in human clinical trials or used as FDA-approved drugs.

Related Articles

• "Chemical biology at the Broad Institute" Nature Chemical Biology, April 2007
  

Further Reading

• Current Science
  
• archive Research Detail
  
• Stuart L. Schreiber biography