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

Shih Chung Yen, Liang Chieh Chen, Han Li Huang, Wei Chun HuangFu, Yi Ying Chen, Tony Eight Lin, Ssu Ting Lien, Hui Ju Tseng, Tzu Ying Sung, Jui Hua Hsieh, Wei Jan Huang, Shiow Lin Pan, Kai Cheng Hsu

Research output: Contribution to journalArticlepeer-review

Abstract

Fms-like tyrosine kinase 3 (FLT3) is considered a promising therapeutic target for acute myeloid leukemia (AML) in the clinical. However, monotherapy with FLT3 inhibitor is usually accompanied by drug resistance. Dual inhibitors might be therapeutically beneficial to patients with AML due to their ability to overcome drug resistance. Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) phosphorylate eukaryotic translation initiation factor 4E (eIF4E), which brings together the RAS/RAF/ERK and PI3K/AKT/mTOR oncogenic pathways. Therefore, dual inhibition of FLT3 and MNK2 might have an additive effect against AML. Herein, a structure-based virtual screening approach was performed to identify dual inhibitors of FLT3 and MNK2 from the ChemDiv database. Compound K783-0308 was identified as a dual inhibitor of FLT3 and MNK2 with IC50 values of 680 and 406 nM, respectively. In addition, the compound showed selectivity for both FLT3 and MNK2 in a panel of 82 kinases. The structure-activity relationship analysis and common interactions revealed interactions between K783-0308 analogs and FLT3 and MNK2. Furthermore, K783-0308 inhibited MV-4-11 and MOLM-13 AML cell growth and induced G0/G1 cell cycle arrest. Taken together, the dual inhibitor K783-0308 showed promising results and can be potentially optimized as a lead compound for AML treatment.

Original languageEnglish
Article number105675
JournalBioorganic Chemistry
Volume121
DOIs
Publication statusPublished - Apr 2022

Keywords

  • Acute myeloid leukemia
  • Dual inhibitors
  • FLT3 inhibitors
  • MNK2 inhibitors
  • Structure-based virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Identification of a dual FLT3 and MNK2 inhibitor for acute myeloid leukemia treatment using a structure-based virtual screening approach'. Together they form a unique fingerprint.

Cite this