A small molecule approach to spatial and temporal control of covalent protein inhibition in cells

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Small molecules that covalently modify proteins are valuable therapeutics and chemical probes for biological discovery. For example, broad-spectrum reactive probes can be used to identify new ligandable sites in proteins that could be targeted by small molecules, and to profile protein modifications that nature uses to modulate protein function. Covalent inhibitors that modify a protein target are an important and growing class of drugs. However, these inhibitors are always "on". The conformations, modifications and locations of proteins in cells are key determinants of biological function, and the goal of this project is to develop a covalent inhibitor that can be switched on in the cell to study the biology of a protein in a defined location and at a specific time. This project will develop chemistry to label protein cysteines in cells using covalent inhibitors with spatial and temporal control. Cysteines are the most frequently targeted residue in covalent inhibitors and are functionally interesting residues that are involved in redox processes and other protein modifications in biology. We will cage cysteine-reactive inhibitors, generating compounds that can enter cells and subsequently be uncaged at a time and place of our choosing to label proteins. This approach would allow us to overcome the potential broad toxicity of covalent probes, and control the time and location (e.g. organelle or tissue) of inhibition.