Stuart L. Schreiber
Wolf Prize Laureate in Chemistry 2016
Stuart L. Schreiber
Affiliation at the time of the award:
Harvard University, Cambridge, MA, USA
“For pioneering chemical insights into the logic of signal transduction and gene regulation that led to important, new therapeutics, and for advancing chemical biology and medicine through the discovery of small-molecule probes”.
Prof. Stuart L. Schreiber contributions to chemistry, broadly defined, are of a once-in-a-generation magnitude. As one of the earliest chemical biologists, Professor Schreiber’s research led to multiple major discoveries that continue to define and drive the field forward. He discovered the FKBPs, proteins that bind FK506, a highly complex small molecule synthesized in Professor Schreiber’s laboratory. The resulting insights identified the signaling pathway that links calcium, calcineurin, and NFAT. Both the biology underlying this pathway, as well as the chemical approach used to illuminate it, have served as a foundation for many other investigations in hundreds of laboratories and has led to the use of FK506 and rapamycin as immunosuppressive and antiproliferative drugs. Professor Schreiber’s subsequent work in elucidating biological pathways using small molecules has led to major discoveries in understanding the biology of nutrient sensing and immunosuppression, including the discovery of the protein kinase mTOR, which regulates cell proliferation, cell survival, transcription, and translation, as well as the discovery that small-molecule drugs can target protein kinases such as mTOR. The discoveries themselves have revealed fundamental cellular signaling and gene regulatory pathways and dramatically advanced the understanding of the role these pathways play in human diseases. It should be emphasized that these findings have been perceived at the time as extremely challenging. Professor Schreiber’s research also yielded the discovery of the first selective proteasome inhibitor lactacystin and the discovery of the long sought after histone deacetylases (HDAC1) using a synthetic variant of the small-molecule trapoxin. His work highlighted the similarities of intracellular and chromatin “signaling”. The discoveries that HDACs and HATs (the latter by David Allis also in 1996) are transcriptional regulators changed the perception of chromatin from a simple structural element to a key geneexpression regulatory element and facilitated the development of vorinostat and romidepsin, drugs that target previously considered ‘undruggable’ gene expression via HDACs. Professor Schreiber’s scientific advances have proven foundational for therapeutic development, including the proteasome inhibitor bortezomib, kinesin-5 inhibitors, and HDAC6 inhibitors, which are all currently in clinical trials. Schreiber developed the ‘bump/hole’ strategy for creating allele-specific small molecules. He conceived and developed diversity-oriented synthesis (DOS), which in the past three years has been the basis for the discovery of the field’s most remarkable new probes, including in vivo probes, with dozens of examples of novel activities in compounds that would otherwise have escaped discovery. Professor Stuart Schreiber’s seminal scientific accomplishments, visionary linkage of synthetic chemistry and biology, and role in advancing the field of chemical biology have transformed chemistry, biology, physiology and medicine and are the basis of this nomination.