Exploring the Resistance Mechanisms of Distal D835V Mutation in FLT3 to Inhibitors.

ABSTRACT:

Objective

FMS-like tyrosine kinase 3 (FLT3) is an attractive therapeutic target in acute myeloid leukemia. Unfortunately, secondary FLT3 mutations that developed resistance to inhibitors have become a severe problem. Specifically, ASP-835 (D835F/H/V/Y) mutant within the activation loop of FLT3 is the most commonly encountered drug-resistant and observed secondary FLT3 mutations. In this study, we carried out a set of computational approaches to explore how this mutation influenced the conformation and dynamics of DFG motif in a manner altered inhibitors' susceptibility.

Methods

Molecular dynamics (MD) simulation, dynamic cross-correlation (DCC) analysis, surface area (SASA), binding free energy (MM-GBSA), and structural analysis were used to compare the severe and minor D835

SUBMITTER: Wang Z 

PROVIDER: S-EPMC8979743 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature