Insight into the inhibitor discrimination by FLT3 F691L

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase crucial for hematopoietic progenitor cells.
• Mutations in FLT3, particularly the F691L kinase domain mutation, are implicated in ~30% of acute myeloid leukemia (AML) cases and confer resistance to FLT3 inhibitors like quizartinib.

Purpose of the Study:

• To investigate the molecular interactions of FLT3 F691L with inhibitors MZH29 and crenolanib.
• To compare the binding stability and efficacy of MZH29 and crenolanib against quizartinib for FLT3 F691L.

Main Methods:

• Molecular dynamics simulations and binding energy calculations were employed.
• Free energy landscape analysis was performed to assess binding stability.

Main Results:

• The residues Glu661 and Asp829 were identified as critical for FLT3 F691L binding with MZH29 and crenolanib, contributing significantly to binding energy.
• These key interactions were notably absent in the binding of quizartinib to FLT3 F691L.
• FLT3 F691L demonstrated more stable binding with MZH29 and crenolanib compared to quizartinib.

Conclusions:

• MZH29 and crenolanib exhibit distinct and favorable binding interactions with the FLT3 F691L mutation.
• These findings suggest MZH29 and crenolanib as promising candidates for overcoming acquired resistance to FLT3 inhibitors in AML.