Schreiber Group Research Overview, 2009.
Current and future collaborative research in the Schreiber group focuses 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, we develop and perform organic synthesis ("diversity synthesis") that anticipates the needs for chemistry at each stage.
In the very 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 using short, modular pathways have features 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.
Overall, the Schreiber group is developing two types of technologies that enable the implementation of a new conceptual approach to two major disease areas:
Development of next-generation synthetic chemistry affording a transformative 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, 3) and 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. The Schreiber 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. Overall, the 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 use the public database ChemBank to determine the role of origins of compounds in assay performance, among others.
Investigating small molecules using human primary cells 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 state changes that are of interest, for example, developmental states. We and our collaborators are developing assays that use human primary cells and tissues, often using combinations of cells (heterotypic culturing) to explore pancreatic beta cell biology, leukemic stem cells, metastasis of breast cancer, drug resistance in multiple myeloma, among others.
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 using attaching chemistry and biasing elements, developing new types of screens; e.g., multiplexed targeting of therapeutic RNAs, among others, to change chromatin states of cells. We aim to alter cell states via changes in chromatin marks at key genes.
Diabetes and cancer. Using this small molecule-based approach, we are attempting to convert human pancreatic acinar or alpha cells into glucose-responsive, insulin-secreting beta (or beta-like) cells by this approach. In related studies, we are attempting to discover small molecules that increase pancreatic beta cell numbers and function using organ cultures of human primary pancreatic islets. These efforts aim to discover small molecules that affect human islet function as a means to treat T1D and T2D. We are also attempting to discover small molecules that modulate cancer cells and cancer stem cells in environments that mimic their in vivo niche. We are targeting oncogenic signaling pathways/oncogenes and transcription factors classic examples of what are often viewed as undruggable targets. Together with collaborators, we aim to discover small molecules that affect human cancer cells as a means to treat cancer.
- "Small molecules for big medicines" HHMI Bulletin, May 2008
- "The gap between scientists' aspirations and society's expectations" CHEMBIOCHEM, 2009
- "Molecular diversity by design" Nature, January 2009
- "Towards the optimal screening collection: a synthesis strategy" Agnew. Chem., 2008
- "Small molecules: the missing link in the central dogma" Nature Chemical Biology, July 2005