Abstract

Irreversible chemical probes are powerful tools for investigating protein function and may even serve as lead compounds for future drugs. We recently reported two complementary quantitative chemical proteomics platforms that enable proteome-wide assessment of the reactivity and ligandability of cysteine and lysine residues (1,2). Application of these platforms has identified lead fragment electrophiles for hundreds of proteins in parallel, including proteins involved in cancer metabolism, protein-protein interactions and pro-caspases. Taking an interdisciplinary approach that merges proteomics, genomics, and cysteine-reactive chemical probes, our current research aims to develop next generation chemical probes and to dramatically expand the landscape of human proteins accessible to probes. Here I will discuss the synthesis of new custom chemical reporters and the development of new chemical proteomic methods that together guide the production of probes that rewire protein function in new and surprising ways.

1. Backus, K. M., Correia, B. E., Lum, K. M., Forli, S., Horning, B. D., Gonzalez-Paez, G. E., Chatterjee, S., Lanning, B. R., Teijaro, J. R., Olson, A. J., Wolan, D. W., and Cravatt, B. F. (2016) Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570-574
2. Hacker, S. M., Backus, K. M., Lazear, M. R., Forli, S., Correia, B. E., and Cravatt, B. F. (2017) Global profiling of lysine reactivity and ligandability in the human proteome. Nature Chemistry 9, 1181-1190