Thursday, October 15, 2020

Assessment of tractable cysteines by covalent fragments screening

Petri, L., Ábrányi-Balogh, P., Imre, T., Pálfy, G., Perczel, A., Knez, D., Hrast, M., Gobec, M., Sosič, I., Nyíri, K., Vértessy, B..G., Jänsch, N., Desczyk, C., Meyer-Almes, F., Ogris, I., Grdadolnik, S..G., Iacovino, L..G., Binda, C., Gobec, S. and Keserű, G..M. 

ChemBioChem. 2020

 doi:10.1002/cbic.202000700

Targeted covalent inhibition and the use of irreversible chemical probes are important strategies in chemical biology and drug discovery. To date, the availability and reactivity of cysteine residues amenable for covalent targeting have been evaluated by proteomic and computational tools. Here, we present a toolbox of fragments containing a 3,5‐bis(trifluoromethyl)phenyl core that was equipped with chemically diverse electrophilic warheads showing a range of reactivities. We characterized the library members for their reactivity, aqueous stability and specificity for nucleophilic amino acids. By screening this library against a set of enzymes amenable for covalent inhibition, we showed that this approach experimentally characterized the accessibility and reactivity of targeted cysteines. Interesting covalent fragment hits were obtained for all investigated cysteine‐containing enzymes.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...