Optimizing the selectivity of kinase inhibitors is a major challenge in kinase drug development, which is mostly due to sequence and structural similarity in the ATP-binding sites across the kinome. Although compounds can show similar inhibitory activity (IC₅₀s) or binding affinities (K_Ds) at equilibrium, these values can consist of very different binding kinetics(association constant: kon/dissociation constant: koff). Given this, designing drugs with desirable selectivity profiles should not only require an appropriate binding selectivity but also the modulation of kinetic selectivity. It is well understood that the longer a compound binds a target, the greater its potential effect - and this is represented by the half life or residence time of the interaction (1/koff). Optimizing a compound to increase its residence time is therefore a key early step in drug discovery programs. NanoBRET™ TE Intracellular Residence Time Analysis provides a mechanism to optimize the residence time of compounds against individual kinase targets, in a living cellular environment.

Data analysis method reference
A New Method to Determine Drug-Target Residence Time of Kinase Inhibitors in Living Cell
(AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2019)

(Note)
Prior to Residence Time (RT) Analysis, your compound's IC₅₀ must be determined using our NanoBRET™ assay platform to obtain the ideal concentration for RT optimized assay performance. Our IC₅₀ determinations are performed using half-log dilutions and eight(8) compound concentrations. Depending on the determined IC₅₀ of your compound, we may not be able to perform Residence Time Analysis on it.

Please consult us for details about your residence time analysis request.