Chemical probes offer a valuable way to directly interrogate the function and disease-relevance of proteins and they can also serve as valuable leads for new therapies, yet most proteins in the human proteome lack small-molecule tools to study their function. More generally, the boundaries, if any, on the “druggability” across the proteome remain poorly understood. The Parker lab aims to develop various chemical probes and integrate them with powerful proteomic methods in effort to expand our understanding of what can be considered the druggable proteome. Resulting chemical tools will be used to interrogate the function and contributions of proteins that have pathophysiological roles in human disease, such as cancer and immune diseases, but currently lack useful chemical probes.
Identification of new druggable proteins
The identification of new pharmacologically actionable targets remains a top priority for academia and pharma/biotech alike. A major hurdle continues to be sufficient exploration of chemical space as well as understanding the interactions of compounds in native environments. The Parker Lab utilizes various chemical proteomic strategies to map the interactions of small molecules with proteins in order to identify new pharmacologcially actionable targets. We adopt features of fragment-based ligand discovery (FBLD) to efficiently explore biologically relevant chemical space directly in living cells to identify proteins, and sites on proteins, capable of interacting with drug-like small molecules. This information can then be advanced to generate more selective and potent chemical probes. We also extend this approach to identify the targets bioactive small molecules, such as metabolites and screening hits, to understand their influence on protein function.
Chemical proteomic approach to study transporters
Low molecular weight molecules (e.g. amino acids, sugars, lipids, metals, nucleotides, etc) play essential roles in cellular signaling, metabolism and communication. Disease is often associated with the dysregulation of these molecules, thus new strategies to study and control their regulation could prove valuable for therapeutic intervention. Transporters can be considered molecular gates of the cell, allowing these molecules to traverse through cellular barriers (i.e. membranes), thus serving as crucial points of control for various processes. However, despite their critical functions and therapeutic promise, many transporters, such as the solute carrier (SLC) super family, remain largely underexplored. Using powerful fragment-based chemical proteomic platforms from our lab, we are developing chemical probes to explore SLC function in the context of basic cellular biology and disease pathways .
Bifunctional small molecules to alter protein function
Most chemical probes directly inhibit, and sometimes enhance, protein activity. We are leveraging our chemical proteomic platforms to develop bifunctional molecules to redirect protein activity or endow them with new function in order to investigate various biological processes.