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Chemical Biology
Summary: Stuart Schreiber's lab has developed systematic ways to use small molecules (precursors to therapeutic drugs that are used as bioprobes) to explore cell circuitry and disease biology. His lab is also known for having helped develop the area of chemical biology. Using his chemical approach, he has discovered principles that underlie information transfer and storage in cells.
Current and future collaborative research in my group is focused on diabetes and cancer, where small molecules that target the epigenome are used to alter the states of human primary cells and tissues. As these studies rely on small molecules at many stages of our research, trainees in my lab develop and perform organic synthesis ("diversity synthesis") that anticipates the needs for chemistry at each stage.
In the first step of this research, before biological studies are undertaken, we contribute to the synthesis of a small-molecule screening collection whose purpose is to enable the discovery of small molecules that modulate nearly any aspect of human biology in which one might have an interest. Due to their stereochemically and skeletally diverse structures, these compounds collectively provide valuable structure/activity relationships, including those derived from stereochemistry, from primary small-molecule screens. The compounds we synthesize have features, and are derived from short, modular pathways, that facilitate their optimization in follow-up biological investigations. They also have features that facilitate the identification of the protein targets to which they bind or that enable their targeting to families of proteins—for example, to chromatin-modifying enzymes.
My group is developing two methods that enable the implementation of a new conceptual approach to two major disease areas.
Development of Synthetic Chemistry That Yields an Optimal Small-Molecule Screening Collection
The development of effective small-molecule probes and drugs entails at least three stages: (1) a discovery phase, often requiring the synthesis and screening of candidate compounds, (2) an optimization phase, requiring the synthesis and analysis of structural variants, and (3) a manufacturing phase, requiring the efficient, large-scale synthesis of the optimized probe or drug. In the pharmaceutical industry, specialized project groups tend to undertake the individual activities without prior coordination; for example, contracted (outsourced) chemists may perform the first activity while in-house medicinal and process chemists perform the second and third development stages, respectively. The coordinated planning of these activities in advance of the first small-molecule screen tends not to be undertaken, and each project group can encounter a bottleneck that could, in principle, have been avoided with advance planning.
My group has been developing a new kind of chemistry that aims to yield a screening collection comprising small molecules that increase the probability of success in all three phases. 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, and general barriers such as "undruggable targets." (Are undruggable targets undruggable, or are they the consequence of an insufficient drug-discovery process?) 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 others.
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 are developing 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 do we exploit the remarkable ability of genetic approaches—including whole-genome association studies in human genetics, cancer 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
We are attempting to convert human alpha 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. These efforts aim to discover small molecules that affect human islet function as a means to treat type-1 and type-2 diabetes. We are also attempting to discover small molecules that modulate cancer cells and cancer stem cells in environments that mimic their in vivo niche. With collaborators, we aim to discover, as a means to treat cancer, small molecules that affect human cancer cells.
Last updated: September 8, 2008
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