Wednesday, July 29, 2020

Multiparameter kinetic analysis for covalent fragment optimization using quantitative irreversible tethering (qIT)

Craven, G..B., Affron, D..P., Kösel, T., Wong, T.L..M., Jukes, Z..H., Liu, C., Morgan, R..M.L., Armstrong, A. and Mann, D..J. 
ChemBioChem, 2020 
doi:10.1002/cbic.202000457

Covalent fragments are increasingly being implemented to develop chemical probes but the complex relationship between fragment structure and binding kinetics makes optimization uniquely challenging. We describe a new technique in covalent probe discovery that enables data driven optimization of covalent fragment potency and selectivity. This platform extends beyond the existing methods for covalent fragment hit identification by facilitating rapid multiparameter kinetic analysis of covalent structure‐activity relationships through simultaneous determination of Ki, kinact and intrinsic reactivity. We apply this approach to develop novel probes against electrophile sensitive kinases and showcase how multiparameter kinetic analysis enabled a successful fragment merging strategy.

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...