Last update 01 Nov 2024

FLT3 x MNK2

Last update 01 Nov 2024

Basic Info

Related Targets

FLT3MNK2

Drugs associated with FLT3 x MNK2

K783-0308

Target

FLT3 x MNK2

Mechanism

FLT3 inhibitors [+1]

Active Org.

Taipei Medical University

Originator Org.

Taipei Medical University

Active Indication

Myeloid Leukemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with FLT3 x MNK2

100 Translational Medicine associated with FLT3 x MNK2

0 Patents (Medical) associated with FLT3 x MNK2

Literatures (Medical) associated with FLT3 x MNK2

01 Jun 2022·PhytomedicineQ2 · MEDICINE

O-methylated flavonol as a multi-kinase inhibitor of leukemogenic kinases exhibits a potential treatment for acute myeloid leukemia

Q2 · MEDICINE

Article

Author: Chu, Jung-Chun ; Lin, Tony Eight ; Yang, Chia-Ron ; Wu, Yi-Wen ; Hsu, Kai-Cheng ; Tu, Huang-Ju ; Chao, Min-Wu ; HuangFu, Wei-Chun ; Sung, Tzu-Ying ; Tseng, Hui-Ju ; Chen, Liang-Chieh ; Huang, Cheng-Chiao ; Pan, Shiow-Lin ; Yen, Shih-Chung ; Huang, Wei-Jan

BACKGROUNDAcute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications.PURPOSEIn this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells.METHODSThe cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively.RESULTSIn this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC₅₀ values of 1 - 2 μM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G₀/G₁ phase and followed by the cells undergoing apoptosis.CONCLUSIONO-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization.

01 Apr 2022·Bioorganic ChemistryQ2 · CHEMISTRY

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

Q2 · CHEMISTRY

Article

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

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.

01 Oct 2017·European Journal of Medicinal ChemistryQ1 · MEDICINE

Dual Inhibition of Mnk2 and FLT3 for potential treatment of acute myeloid leukaemia

Q1 · MEDICINE

Article

Author: Albrecht, Hugo ; Noll, Ben ; Yu, Mingfeng ; Diab, Sarah ; Milne, Robert W ; Rahaman, Muhammed H ; Abdelaziz, Ahmad M ; Li, Peng ; Teo, Theodosia ; Le, Bich T ; Hou, Jinqiang ; Lu, Jingfeng ; Wang, Shudong ; Basnet, Sunita K C

The discovery of novel anti-AML therapeutic agents is urgently needed, but the complex heterogeneity of the disease has so far hampered the development of a curative treatment. FLT3 inhibitors have shown therapeutic potential in clinical trials; but a monotherapy regimen has been associated with resistance mediated by the activation of parallel signalling circuitry, including MAPK and mTOR. Therefore, inhibiting a nexus of the two signalling pathways along with inhibition of FLT3 might be advantageous. Herein, we propose that a dual inhibition of FLT3 and Mnk would provide a better clinical option for AML patients compared to targeting FLT3 alone. Thus, a series of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines and 4-(indol-3-yl)-N-phenylpyrimidin-2-amines were prepared. Potent Mnk2 inhibitors, FLT3 inhibitors, and dual inhibitors of Mnk2 and FLT3 were identified and their anti-proliferative activities assessed against MV4-11 AML cell lines. Dual inhibition of FLT3 and Mnk2 caused the increased apoptotic cell death of MV4-11 cells compared to inhibition of FLT3 or Mnk2 alone.

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