Schreiber started his research work in organic synthesis, focusing on concepts such as the use of Woodward-Hoffmann rules|[2 + 2] photocycloadditions to establish
stereochemistry in complex molecules, the fragmentation of hydroperoxides to produce
macrolides, ancillary stereocontrol, group selectivity and two-directional synthesis. Notable accomplishments include the total syntheses of complex natural products such as periplanone B, talaromycin B, asteltoxin, avenaciolide, gloeosporone, hikizimicin, mycoticin A, epoxydictymene and the immunosuppressant
FK-506. Following his work on 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-ciclosporin-calcineurin. This work, together with work by
Gerald Crabtree at
Stanford University concerning the
NFAT proteins, led to the elucidation of the calcium-
calcineurin-
NFAT signaling pathway. The Ras-Raf-MAPK pathway was not elucidated for another year. In 1993, Schreiber and Crabtree developed bifunctional molecules or “chemical inducers of proximity” (CIPs), which provide small-molecule activation over numerous signaling molecules and pathways (e.g., the Fas, insulin,
TGFβ and T-cell receptors) through proximity effects. Schreiber and Crabtree demonstrated that small molecules could activate a signaling pathway in an animal with temporal and spatial control. Dimerizer kits have been distributed freely resulting in many peer-reviewed publications. Its promise in gene therapy has been highlighted by the ability of a small molecule to activate a small-molecule regulated EPO receptor and to induce
erythropoiesis (
Ariad Pharmaceuticals, Inc.), and more recently in human clinical trials for treatment of graft-vs-host disease. In 1994, Schreiber and co-workers investigated (independently with
David Sabitini) the master regulator of nutrient sensing, mTOR. They 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 illuminated the nutrient-response signaling network involving TOR proteins in yeast and mTOR in mammalian cells. Small molecules such as uretupamine and rapamycin were shown to be particularly effective in revealing the ability of proteins such as mTOR, Tor1p, Tor2p, and Ure2p to receive multiple inputs and to process them appropriately towards multiple outputs (in analogy to 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 1995, Schreiber and co-workers found that the small molecule
lactacystin binds and inhibits specific catalytic subunits of the
proteasome, a protein complex responsible for the bulk of proteolysis in the cell, as well as proteolytic activation of certain protein substrates. As a non-peptidic proteasome inhibitor lactacysin has proven useful in the study of proteasome function. Lactacystin modifies the amino-terminal threonine of specific proteasome subunits. This work helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal
threonine protease. The work led to the use of
bortezomib to treat
multiple myeloma. In 1996, Schreiber and co-workers used the small molecules trapoxin and depudecin to investigate the
histone deacetylases (HDACs). Prior to Schreiber's work in this area, the HDAC proteins had not been isolated. Coincident with the HDAC work,
Charles David Allis and colleagues reported work on 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
Brian D. Strahl and
Charles David Allis. These studies shined a bright light on
chromatin as a key gene expression regulatory element rather than simply a structural element used for DNA compaction. ==Diversity-oriented synthesis==