Summary: Stuart Schreiber's lab has developed systematic ways to use small molecules (precursors to therapeutic drugs that are used as probes) to explore cell circuitry and disease biology. Using his chemical approach, he has discovered principles that underlie information transfer and storage in cells.
Development of Synthetic Chemistry That Yields a Transformative Small-Molecule Screening Collection
My group has been developing a new kind of chemistry that yields a screening collection comprising small molecules that increase the probability of success in all three phases of discovery in which chemistry plays a role (discovery, optimization, and manufacturing). Our goal is to be able to modulate any aspect of human biology in which one might have an interest, overcoming current perceived barriers associated with specific challenges, such as small-molecule disruption of protein-protein interactions. We developed the public database ChemBank in order to provide public access to our screening data. We use ChemBank to determine the role of origins of compounds in assay performance, among other applications.
The Use of Human Primary Cells to Investigate Small Molecules in an Environment That Mimics Their In Vivo Niche
Phenotypic screens are typically performed using cell lines. In certain cases, cell lines may be inadequate to reveal the changes that are of interest—for example, developmental states. We have developed assays that use human primary cells and tissues, often using combinations of cells (heterotypic culturing) to explore beta-cell biology, leukemic stem cells, metastasis of breast cancer, and drug resistance in multiple myeloma.
From Genes to Therapeutics through Chromatin
How can we exploit the remarkable ability of genetic approaches—including human genetics, cancer and microbial genomics, and mouse genetics in developmental biology—to illuminate the roles of genes in biology and disease? We are exploring a new concept that relies on small molecules that alter specific chromatin marks at the sites of these genes, especially at master regulatory genes. We aim to determine whether cell states can be altered in vivo by small molecules that target the epigenome. We are exploiting our up-front investment in diversity synthesis by modifying the resulting compounds, using chemistry that attaches chromatin-targeting biasing elements. We are also developing new types of screens (e.g., multiplexed targeting of therapeutic RNAs) in order to detect changes in the chromatin states of cells. We aim to alter cell states via changes in chromatin marks at key genes.
Diabetes and Cancer
In diabetes studies, we are attempting to convert human alpha cells, or other pancreatic cells, into glucose-responsive, insulin-secreting beta (or beta-like) cells. In related studies, we are attempting to use organ cultures of human primary pancreatic islets to discover small molecules that increase pancreatic beta-cell numbers and function and that spare the beta cells from cytokine-induced death. These efforts aim to discover small molecules that affect human islet function as a means to treat type-1 and type-2 diabetes. In cancer studies, we are using 1,000 genomically characterized cancer cell lines and hundreds of highly specific small-molecule probes to determine the genetic features of cancer that specify small-molecule sensitivity. Our goal is to understand the relationship of the genetic features of human cancers (mutations; copy number variants; gene expression) to drug efficacy comprehensively.
Grants from the National Cancer Institute, the Juvenile Diabetes Research Foundation, and the National Institute of General Medical Sciences provided partial support for the work on cancer, diabetes, and diversity synthesis, respectively.
As of May 30, 2012