Wednesday, June 17, 2020

In Vivo Imaging of the Tumor‐Associated Enzyme NCEH1 with a Covalent PET Probe

Chang, J.W., Bhuiyan, M., Tsai, H.‐M., Zhang, H.J., Li, G., Fathi, S., McCutcheon, D.C., Leoni, L., Freifelder, R., Chen, C.‐T. and Moellering, R.E. 

Angew. Chem. Int. Ed. 2020
Herein, we report the development of an 18F‐labeled, activity‐based small‐molecule probe targeting the cancer‐associated serine hydrolase NCEH1. We undertook a focused medicinal chemistry campaign to simultaneously preserve potent and specific NCEH1 labeling in live cells and animals, while permitting facile 18F radionuclide incorporation required for PET imaging. The resulting molecule, [18F]JW199, labels active NCEH1 in live cells at nanomolar concentrations and greater than 1000‐fold selectivity relative to other serine hydrolases. [18F]JW199 displays rapid, NCEH1‐dependent accumulation in mouse tissues. Finally, we demonstrate that [18F]JW199 labels aggressive cancer tumor cells in vivo, which uncovered localized NCEH1 activity at the leading edge of triple‐negative breast cancer tumors, suggesting roles for NCEH1 in tumor aggressiveness and metastasis.

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 Covalent drug discovery has ...