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

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

Applications of Catalytic Organometallic C(sp3)–H Bond Functionalization

The transition-metal-catalyzed activation of C(sp3)–H bonds has emerged as powerful strategy to create bonds and introduce functional groups in a direct fashion. This review focuses on recent applications of C(sp3)–H bond functionalization strategies to the synthesis of biologically active and natural compounds