Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects.

ABSTRACT: Optimization exercises strive toward increasing the efficacy and selectivity of small molecules toward the target of interest while simultaneously phasing out design elements that lead to off-target interactions. Given the nonequilibrium nature of biological systems, greater reliance should be placed on engineering kinetic selectivity in addition to equilibrium thermodynamic selectivity; however, the rational design of kinetic selectivity is a challenging endeavor. This study presents a systematic knowledge-based approach to the design of inhibitors that vary in their binding kinetics for Bruton's tyrosine kinase (BTK), a target for treating B-cell malignancies and autoimmune diseases. A detailed kinetic assessment was performed on existing BTK inhibitors, which, together with structural s

SUBMITTER: Bravo E 

PROVIDER: S-EPMC12709725 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature