Tuesday, June 6, 2023

Comprehensive Mapping of Electrophilic Small Molecule-Protein Interactions in Human Cells

Cravatt, B.; Njomen, E.; Hayward, R.; DeMeester, K.; Ogasawara, D.; Dix, M.; Nguyen, T.; Ashby, P.; Simon, G.; Schreiber, S.; Melillo, B. 

ChemRxiv 2023

https://doi.org/10.26434/chemrxiv-2023-s446n

Covalent chemistry is a versatile approach for expanding the ligandability of the human proteome. Activity-based protein profiling (ABPP) can infer the specific residues modified by electrophilic compounds through competition with broadly reactive probes. Nonetheless, the extent to which such residue-directed ABPP platforms fully assess the protein targets of electrophilic compounds in human cells remains unclear. Here, we introduce a complementary approach that directly identifies proteins showing stereoselective reactivity with focused libraries of stereochemically-defined, alkynylated electrophilic compounds. Integration of protein- and cysteine-directed ABPP data from compound-treated human cancer cells revealed generally well-correlated target maps and highlighted specific features, such as protein size and the proteotypicity of cysteine-containing peptides, that help to explain gaps in each ABPP platform. The integrated ABPP strategy furnished stereoselective, high-engagement covalent ligands for > 300 structurally and functionally diverse human proteins, including compounds that modulate enzymes by canonical (active-site cysteine) and non-canonical (isotype-restricted and non-catalytic cysteines) mechanisms.



Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation

Gregory B. Craven, Hang Chu, Jessica D. Sun, Jordan D. Carelli, Brittany Coyne, Hao Chen, Ying Chen, Xiaolei Ma, Subhamoy Das, Wayne Kong, A...