Abstract
Selectivity of kinase
inhibitors is one of the main challenges faced by researchers, often making it
difficult to balance potency and pharmacokinetics while avoiding severe
toxicity. It is now understood that drug safety in the human body is difficult
to achieve by solely taking into account affinity. Indeed, there is growing
evidence for the physiological relevance of the interplay between binding
kinetics and pharmacokinetic parameters.
By using only the
affinity constant, researchers not only miss the opportunity to modulate target
selectivity but also perturb the duration of action and tune the therapeutic index
through modification of binding kinetics.
Which drug crosses
the line first, the fast-acting hare or the slow-moving tortoise? With this
question in mind, we decided to study if the early evaluation of binding
kinetics is a powerful tool to improve decision-making. We have found that compounds
with identical affinity towards multiple kinases can exhibit dramatically
different kinetics such that the on and off-rates of the drug-target complexes
differ by orders of magnitude. This means that kinetic selectivity can still
exist even in the absence of binding selectivity. The implicit relationship
between selectivity and therapeutic index makes this fact extremely useful and
demands that kinetic selectivity also be taken into account.
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