Building better models to define therapeutic windows
It is now understood that drug safety is difficult to achieve by solely considering affinity1-3. Indeed, many reports link selectivity to the kinetic profile of the drugs4-15.
Selectivity is highly dynamic in the human body and evolves over the course of treatment as a function of the temporal binding between the drug and on- and off-targets.
- As a result, therapeutic window is maximized when a drug shows long residence time when bound to its main target and short residence times for secondary targets.
- In contrast, a drug that displays a long residence time against a toxicity-mediating target will result in safety issues.
Affinity doesn’t tell the whole story of MET inhibitor Foretinib
The MET pathway is a promising target in Papillary Renal cell carcinoma (PRCC). Foretinib at 240 mg orally once per day on days 1 to 5 every 14 days (Cmax=300 nM) has demonstrated activity in patients with PRCC with a manageable toxicity profile and a high response rate in patients with germline METmutations16.
To study the effect of residence time on Foretinib’s selectivity profile, we characterized the compound in parallel with 18 different kinases using KINETICfinder®.
|Target||Kd (nM)||kon (M-1s-1)||koff (s-1)||τ (min)||Kd off/on-target||kon off/on-target||τ off/on-target|
Kinetic selectivity can exist even in the absence of affinity selectivity
- As shown in previous studies17, Foretinib binds very tightly to MET kinase (0.96 nM), with a residence time of approximately 24 h.
- Despite Foretinib binding with high affinity (≤100 nM) towards the 18 kinases tested, it exhibits dramatically different kinetics such that the on and off-rates of the drug-target complexes differ by orders of magnitude.
- Considering only affinity interactions, Foretinib seems to bind similarly to all the kinases tested.
- However, when residence time is taken into account a kinetic selectivity pattern is clearly apparent (Fig. 3). Whereas Foretinib dissociates rapidly (20 sec) from the secondary target ABL1, it remains bound to its main target MET for approximately 24 hours.
Residence time provides a better understanding of the in vivo drug behavior
- Although Foretinib can potently inhibit 18 kinases at a therapeutic dose, only MET and to a lesser extent FLT3, KDR, CSFR, PDGFR and CDK9 will show a prolonged inhibition over the course of treatment.
- Consequently, its therapeutic index is maximized, exhibiting a manageable toxicity profile and a high response rate in patients with germline MET mutations.
This study shows how kinetic selectivity can still exist even in the absence of affinity selectivity and highlights the importance of parallel affinity and kinetic profiling for modulating the safety profile and therapeutic window or identifying new therapeutic indications.
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