MD simulations guide design of selective irreversible FGFR1 inhibitors
- Molecular dynamics simulations showed that the P-loop of FGFR1 adopts a conformation distinct from other FGFR subtypes, offering a basis for subtype selectivity.
- Restricting the conformational freedom of the linker led to compound 24, a potent and selective covalent FGFR1 inhibitor.
- Simulations indicated its warhead sits well placed to react with the P-loop cysteine, and the covalent adduct keeps hinge binding while fitting the FGFR1-specific conformation.
- Compound 24 suppressed FGFR1-driven tumor growth in cells and in CDX and PDX models.
💡 Points
Going after a P-loop cysteine shaped differently in FGFR1 buys subtype selectivity that a reversible hinge binder struggles to deliver. What worries me is how much of the story rests on simulation. Was selectivity measured across the kinome, and is the warhead tuned mildly enough to avoid off-target reactivity? Rigidifying the linker is the portable lesson I would take to my own series.