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

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.
PMID: 32659037 [PubMed - as supplied by publisher]

Source: Chembiochem - July 12, 2020 Category: Biochemistry Authors: Craven GB, Affron DP, Kösel T, Wong TLM, Jukes ZH, Liu CT, Morgan RML, Armstrong A, Mann DJ Tags: Chembiochem Source Type: research