Stuart L. Schreiber
Stuart Schreiber's lab has reported on a number of small-molecule-based advances, including:
- co-discovering (also: Sol Snyder and David Sabatini) the protein kinase mTOR and illuminating intracellular signaling by mTOR and the protein phosphatase calcineurin (demonstrating for the first time that drugs can result from targeting protein kinases and phosphatases and intracellular signal transduction in general, each perceived as extremely challenging (‘undruggable’) in the 1980s and now a routine and central element of drug discovery);
- conceiving and developing, with Gerald Crabtree, small-molecule dimerizers that activate cellular processes by enforced proximity (widely used in research and now being tested in human clinical trials for treatment of prostate cancer);
- discovering the histone deacetylase-1 (HDAC1) and class II HDACs and illuminating their role in gene regulation (demonstrating for the first time that drugs can result from targeting chromatin-modifying enzymes);
- illuminating the relationship of cancer genotype (initially with mutant RAS) to both cancer metabolic phenotype and small-molecule sensitivities (demonstrating that acquired dependencies of cancers need not be tied to a single oncogene: ‘non-oncogene addiction’);
- developing diversity-oriented synthesis, building on generations of work in synthetic methodology and target-oriented synthesis to create screening candidates whose stereochemical and skeletal structural diversity enabled the discovery of small-molecule probes targeting otherwise challenging targets such as transcription factors, oncogenes, protein/protein and protein/DNA interactions, and chromatin, and processes such as transdifferentiation;
- promoting small-molecule screening in an open data-sharing environment – encouraging current drug discovery activities aimed at causal disease genes and their related processes even when these are viewed as the currently ‘undruggable’ targets)
The primary focus of his group over the next several years will be on: 1) exploring small molecule-mediated transdifferentiation of pancreatic cells in diabetes; 2) developing general approaches for developing small-molecule drugs using insights from human genetics, especially in the context of diabetes and inflammatory bowel disease; and 3) relating the genetic features of human cancers to small-molecule sensitivity comprehensively.
"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.
Last Update: 1/6/2014