1. Identification of a dual FLT3 and MNK2 inhibitor for acute myeloid leukemia treatment using a structure-based virtual screening approach.
- Author
-
Yen SC, Chen LC, Huang HL, HuangFu WC, Chen YY, Eight Lin T, Lien ST, Tseng HJ, Sung TY, Hsieh JH, Huang WJ, Pan SL, and Hsu KC
- Subjects
- Apoptosis, Cell Line, Tumor, Cell Proliferation, Humans, Intracellular Signaling Peptides and Proteins, Mutation, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases, Leukemia, Myeloid, Acute drug therapy, fms-Like Tyrosine Kinase 3
- 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 IC
50 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF