Rational Design of Potent and Highly Selective FGFR1 Irreversible Inhibitors Guided by Molecular Dynamics Simulations

Abstract Molecular dynamics (MD) simulations revealed distinct P-loop conformational differences in the ATP-binding domain between FGFR1 and other FGFR subtypes. A conformation-restricted linker optimization strategy was applied to identify a potent and selective irreversible FGFR1 inhibitor (compound 24). MD models demonstrated that the covalent warhead of compound 24 retained an optimal distance and orientation toward the P-loop cysteine of FGFR1, facilitating efficient Michael addition. After covalent conjugation, compound 24 interacted with the hinge region and precisely matched the unique FGFR1 conformation. Its robust antitumor activity was validated in cellular, CDX, and PDX models by suppressing FGFR1-dependent tumor growth, providing a novel strategy for subtype-selective FGFR1 inhibitor development.