The molecular mechanism behind resistance of the kinase FLT3 to the inhibitor quizartinib.

摘要: Fms-like tyrosine kinase 3 (FLT3) is a receptor that drug target for leukemias. Several potent inhibitors of FLT3 exist, and bind to the inactive form enzyme. Unfortunately, resistance due mutations in domain limits therapeutic effects these inhibitors. As many other cases, it not straightforward explain why certain lead resistance. Extensive fully atomistic molecular dynamics (MD) simulations were carried out with an inhibited (FLT-quizartinib complex), free (apo) form, active conformation. In all both wild type (wt) proteins two resistant mutants (D835F Y842H) studied. Analysis revealed impairment protein-drug interactions cannot question. Rather, appears state mutant forms perturbed by mutations. It therefore likely perturbation deactivation protein (which necessary binding) responsible reduced affinity mutants. Importantly, this study suggests possible source analysis unbiased MD simulations.