Binding Kinetics Survey of the Drugged Kinome

Target
residence time is emerging as an important optimization
parameter in drug discovery, yet target and off-target engagement
dynamics have not been clearly linked to the clinical performance
of drugs. Here we developed high-throughput binding kinetics assays
to characterize the interactions of 270 protein kinase inhibitors
with 40 clinically relevant targets. Analysis of the results revealed
that on-rates are better correlated with affinity than off-rates and
that the fraction of slowly dissociating drug–target complexes
increases from early/preclinical to late stage and FDA-approved compounds,
suggesting distinct contributions by each parameter to clinical success.
Combining binding parameters with PK/ADME properties, we illustrate in silico and in cells how kinetic selectivity could be
exploited as an optimization strategy. Furthermore, using bio- and
chemoinformatics we uncovered structural features influencing rate
constants. Our results underscore the value of binding kinetics information
in rational drug design and provide a resource for future studies
on this subject.