Structure-guided design yields selective wild-type KIT inhibitors that avoid class III RTK off-targets
- Close ATP-site similarity across class III receptor tyrosine kinases makes selective KIT inhibition hard; this work tackles it with structure-guided optimization.
- A triazolopyridine hinge binder gave a selective start, and a central linker change led to a reverse arylacetamide series with better potency and pharmacokinetics.
- A pyrazole linker and hinge-motif edits kept potency in human serum, while terminal aryl tuning reduced CYP time-dependent inhibition and sharpened kinome selectivity.
- Crystal structures showed that linker stereoelectronics near the gatekeeper can drive selectivity, yielding a lead suited to chronic therapy.
💡 Points
The linker, not the hinge binder, is what caught my eye: stereoelectronics near the gatekeeper apparently buy selectivity that ATP-site similarity across class III RTKs would otherwise deny. That is a handle worth stealing for other crowded kinase families. I also like that CYP time-dependent inhibition and human-serum potency were fixed in the same campaign, which reads like a lead meant for chronic dosing.