Deciphering the mechanism of HM43239 inhibiting the mutant F691L resistant to gilteritinib in FMS-like tyrosine kinase 3

Abstract

FMS-like tyrosine kinase (FLT3) has become the legitimate molecular therapeutic target for acute myeloid leukemia therapy. Though FLT3 inhibitors have impact on disease progression, drug resistance induced by secondary point mutations is the primary mechanism and urgent to overcome. Herein, we sought to decipher the mechanism of HM43239 inhibiting the mutant F691L resistant to gilteritinib in FLT3. A series of molecular modeling studies, including molecular dynamics (MD) simulation, dynamic cross-correlation (DCC) analysis, binding free energy (MM-GBSA) and docking study were explored to elucidate the differential tolerance mechanisms of two inhibitors to the same mutant. The F691L mutation had relatively larger effect on gilteritinib than HM43239, which showed as the changed and fixed conformation, respectively. These observations rationalized that the binding affinity of gilteritinib decreased more than that of HM43239 in the F691L mutant.

Communicated by Ramaswamy H. Sarma

Keywords:

• FLT3-ITD
• FLT3-ITD/F691L
• resistance mechanisms
• gilteritinib
• HM43239

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contribution

Jian Wang and Jinghua Lu conceived and supervised the project. Zhiwei Wang analyzed the results and drafted the manuscript. Yu An validated the results. Jian Wang and Jinghua Lu edited and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Additional information

Funding

This work was supported by the Director’s Fund Projects from Liaoning Provincial Key Laboratory of Marine Bioactive Substances and Technological Innovation Center of Liaoning Pharmaceutical Action and Quality Evaluation [2022-11]. This work was performed at the Computer-Aided Drug Design Center of Shenyang Pharmaceutical University.