Identification of a dual FLT3 and MNK2 inhibitor for acute myeloid leukemia treatment using a structure-based virtual...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Fms-like tyrosine kinase 3 (FLT3) is a key therapeutic target in acute myeloid leukemia (AML).
• FLT3 inhibitor monotherapy often leads to drug resistance, necessitating alternative treatment strategies.
• Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) regulate oncogenic pathways crucial for AML progression.

Purpose of the Study:

• To identify novel dual inhibitors targeting both FLT3 and MNK2 for enhanced efficacy in AML treatment.
• To explore the potential of dual inhibition to overcome drug resistance associated with FLT3 inhibitors.
• To evaluate a newly identified compound for its inhibitory effects on AML cell growth and cell cycle progression.

Main Methods:

• Structure-based virtual screening of the ChemDiv database was employed to identify dual FLT3 and MNK2 inhibitors.
• In vitro kinase inhibition assays were performed to determine IC50 values and assess selectivity across a panel of 82 kinases.
• Cell-based assays were conducted to evaluate the compound's effect on AML cell growth and cell cycle arrest.

Main Results:

• Compound K783-0308 was identified as a dual inhibitor of FLT3 and MNK2 with IC50 values of 680 nM and 406 nM, respectively.
• K783-0308 demonstrated selectivity for FLT3 and MNK2 against a broad kinase panel.
• The compound effectively inhibited MV-4-11 and MOLM-13 AML cell growth and induced G0/G1 cell cycle arrest.

Conclusions:

• Dual inhibition of FLT3 and MNK2 presents a promising strategy for overcoming drug resistance in AML.
• Compound K783-0308 exhibits potent dual inhibitory activity and anti-leukemic effects.
• K783-0308 serves as a potential lead compound for further optimization in AML therapeutic development.