Assistant Professor, Genetics - GIDP
In the Chapman laboratory, we are generally interested in developing methodologies to facilitate drug discovery, using chemical biology to study the complex biochemistry and biophysics of protein quality control machinery, and using our chemical and biological tools to discover and study selective inhibitors of medically relevant targets. Students and fellows within our program are engaged in a truly multi-disciplinary effort providing a unique fusion between natural products chemistry, medicinal chemistry, organic synthesis, molecular biology, biochemistry and cellular biology – chemical biology. Our research can be divided into three broad areas:
a) Protein-guided therapeutic discovery. Although proteins are often the primary targets of therapeutic agents, their use often comes very late in the drug discovery process. This is especially true in the discovery of natural product-based therapeutics. We now seek to change this by introducing the protein or proteins of interest at an early stage of the discovery process. Employing a simple concept, long used in cellular and molecular biology, we aim to develop a new platform to discover natural products from marine and terrestrial sources, with future pharmacological potential. This platform will use a protein of interest, based on pharmaceutical potential, linked to a solid support to capture natural products from diverse collectives of purified products and lysates. The captured natural products will then be identified and characterized using state-of-the-art micro-analytical techniques followed by biochemical and cell-biological analysis. This platform will be coupled with the tools of structural genomics to allow access to proteins implicated in many different pathological states. It will also eliminate assay bias and look only for binding, providing a platform to discover natural products with truly novel modes of action, even for traditionally ‘undruggable’ targets.
b) Chemical biology to study p97 biochemistry and biophysics. The ATPase associated with various cellular activities (AAA+) chaperone, p97, is an amazing member of this family. It is a nearly 600 kDa machine that harnesses the energy of ATP-binding and hydrolysis to affect a large and diverse collective of biological functions (i.e. endoplasmic reticulum asscoiated degradation, homotypic membrane fusion, cell-cycle regulation, etc.) and is implicated in numerous pathological states ranging from cancer to neurodegenerative proteinopathies (i.e. Huntington’s disease, ALS, Alzheimer’s disease, etc.). Understanding the underpinnings of these diverse and varied functions and how these correlate with pathological states will provide insight into the disease and guide future drug development efforts. To this end, we are developing a cadre of chemical biology tools to facilitate biochemical and biophysical studies and unfold a detailed mechanistic picture of p97.
c) Small-molecule based therapeutic discovery and development. The University of Arizona has a unique niche in drug discovery with a diverse collective of small-molecules, unique chemistries, and a number of high throughput discovery and development platforms in place. We wish to exploit this expertise and these resources to discover small-molecule inhibitors of two proteins for which we have developed chemical biology tools and biophysical assays that will directly translate to medium to high-throughput small-molecule discovery. The first is p97, discussed above, and the second is α-synuclein, which is associated with Parkinson’s disease. The biophysical tools we develop will allow for discovery of inhibitors with novel modes of action such as interference with protein-protein interactions and blocking structural rearrangements.