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FMS-like tyrosine kinase 3 (FLT3) is an attractive target for acute myeloid leukemia. Recent studies have suggested that the application of small-molecule kinase inhibitors is a promising treatment strategy for patients with primary activating mutations of FLT3; however, the development of secondary mutations, including those of A627T, N676D, F691I, and G697R, that confer acquired resistance to kinase inhibitors has become a severe problem. In this study, we conducted a series of molecular dynamics simulations on PKC412- and sorafenib-bound FLT3 kinases and different apo forms of the FLT3 kinase to explain the minor and severe G697R mutation-induced resistance to sorafenib and PKC412, respectively. Structural analysis on our simulation results revealed that the type II kinase inhibitor sorafenib (IC50 = 9 nM) assesses its binding site through either the adenine pocket entrance or the back pocket entrance, whereas the type I kinase inhibitor PKC412 (IC50 = 35 nM) intercalates to its binding site from the front pocket entrance. The G697 residue is located at the end of the FLT3 kinase hinge segment and is close to the front and adenine pockets. In G697R mutation where the substituted R697 residue affects both the front and adenine pocket entrances in different manners, sorafenib may approach its binding site through the back pocket entrance, whereas PKC412 is blocked by the FLT3 kinase. This observation rationalizes that the kinase activity of the G697R mutant does not decrease in the presence of PKC412 concentrations of up to 400 nM, whereas the IC50 value of sorafenib shifts to 200 nM in response to the same mutation.

A molecular dynamics simulation study for variant drug responses due to FMS-like tyrosine kinase 3 G697R mutation