Stuart Schreiber uses small molecules as probes of biology and medicine, integrating chemical biology and genome biology to understand human disease.
Four key discoveries, 1980’s and 90’s. Following his identification of the FK506-binding protein FKBP12 in 1988, Schreiber 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 Gerald Crabtree’s discovery of the NFAT proteins, led to the elucidation of the calcium-calcineurin-NFAT signaling pathway. This provided an early example of defining an entire cellular signaling pathway from the cell surface to the nucleus, can be appreciated when it is considered that the Ras-Raf-MAPK pathway was not elucidated for another year.
In 1993 Schreiber and Crabtree developed “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. Together, they demonstrated that small molecules could activate a signaling pathway in an animal with temporal and spatial control. Dimerizer kits have been distributed freely to (as of September, 2006) 1,160 laboratories at 461 different institutions in 33 countries.
In 1994, Schreiber found that the small molecule rapamycin simultaneously binds FKBP12 and mTOR (originally named FKBP12-rapamycin binding protein, FRAP). Using diversity-oriented synthesis and small-molecule screening, Schreiber helped illuminate the nutrient-response signaling network involving TOR proteins in yeast and mTOR in mammalian cells. Small molecules such as uretupamine, SMIRs and SMERs (inhibitors and activators of mTOR-regulated 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”). Several pharmaceutical companies are now targeting the nutrient-signaling network for the treatment of several forms of cancer, including solid tumors.
In 1996 Schreiber used the small molecules trapoxin and depudecin to characterize molecularly for the first time the histone deacetylases (HDACs). Prior to Schreiber’s work in this area, the HDAC proteins had not been isolated – despite many 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 much 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 proposed a “signaling network model” of chromatin and compared it to an alternative view, the “histone code hypothesis” presented by Strahl and Allis. This approach also led Schreiber and collaborators to discover novel chromatin methylation patterns (bivalent domains) at the promoters of master regulatory genes in embryonic stem cells. Overall, this research has shined a bright light on chromatin as a key regulatory element central to epigenetics, rather than simply a structural element.
Advancing chemical biology, late 1990’s and 2000’s. Modern methods of organic synthesis and new diversity-oriented synthesis (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 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. DOS and small-molecule screening 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. 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 at the Broad Institute Chemical Biology Program, leading to many small-molecule probes and insights into biology.
To facilitate the open sharing of small-molecule-based insights, the small-molecule and assay-data repository and analysis environment named ChemBank was launched on the Internet in 2003. ChemBank makes accessible to the public (over 43,000 registered users from over 8,000 institutions in 154 countries) results and analyses involving approximately 800,000-curated small molecules, 2,000 small-molecule screens, and 19 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.
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Papers & Publications:
"Signaling network model of chromatin”, S L Schreiber and B E Bernstein, Cell, 2002, 111, 771-778.
“Integration Growth Factor and nutrient signaling: Implications for cancer biology” Alykhan F. Shamji, Paul Nghiem, Stuart L. Schreiber, Molecular Cell, 2003, 12, 271-280.
“Small Molecules: The missing link in the central dogma” S. L. Schreiber, Nat. Chem. Biol., 2005, 1, 64-66. |
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