Design, synthesis and biological evaluation of MNK-PROTACs
Xue Sun1, Qingyun Wu2, Hong Bu2
1Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
Abstract:
Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) can regulate cellular mRNA translation by controlling the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E), which plays an important role in tumor initiation, development, and metastasis. Although small-molecule MNK inhibitors have made significant breakthroughs in the treatment of various malignancies, their clinical application can be limited by drug resistance, target selectivity and other factors. The strategy of MNK-PROTACs which selectively degrades MNK kinases provides a new approach for developing small-molecule drugs for related diseases. In this study, DS33059, a small-molecule compound modified based on the ongoing clinical trials drug ETC-206, was chosen as the target protein ligand. A series of novel MNK-PROTACs were designed, synthesized and evaluated biological activity. Several compounds showed good inhibitory activities against MNK1/2. Besides, compounds exhibited moderate to excellent anti-proliferative activity in A549 and TMD-8 cells in vitro. In particular, compound II-5 significantly inhibited A549 (IC50 = 1.79 μM) and TMD-8 (IC50 = 1.07 μM) cells. The protein degradation assay showed that compound II-5 had good capability to degrade MNK1. The MNK-PROTACs strategy represents a new direction in treating tumors and deserves further exploration.
Insights
New proteolysis-targeting chimeras (PROTACs) offer a novel strategy for cancer treatment by degrading mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs). Compound II-5 demonstrated significant anti-proliferative effects and MNK1 degradation, highlighting the potential of MNK-PROTACs.
Area of Science:
- Molecular Biology
- Oncology
- Medicinal Chemistry
Background:
- Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) regulate mRNA translation via eukaryotic translation initiation factor 4E (eIF4E) phosphorylation, impacting tumor initiation, development, and metastasis.
- Existing small-molecule MNK inhibitors face challenges like drug resistance and target selectivity, necessitating novel therapeutic strategies.
Purpose of the Study:
- To design, synthesize, and evaluate novel MNK-PROTACs as a new therapeutic approach for malignancies.
- To assess the anti-proliferative activity and protein degradation capability of the developed MNK-PROTACs.
Main Methods:
- Design and synthesis of novel MNK-PROTACs utilizing DS33059 as the target protein ligand.
- Evaluation of biological activity, including inhibitory effects against MNK1/2 and anti-proliferative effects in A549 and TMD-8 cancer cell lines.
- Protein degradation assays to confirm the efficacy of the lead compound in degrading MNK1.
Main Results:
- Several synthesized MNK-PROTACs exhibited potent inhibitory activity against MNK1/2.
- Compounds demonstrated moderate to excellent in vitro anti-proliferative activity against A549 and TMD-8 cells.
- Compound II-5 showed significant inhibition (IC50: 1.79 μM in A549, 1.07 μM in TMD-8) and effectively degraded MNK1.
Conclusions:
- The MNK-PROTACs strategy represents a promising new direction for developing targeted cancer therapies.
- Compound II-5 showcases the potential of MNK-PROTACs for treating tumors driven by MNK kinase activity.
- Further exploration of MNK-PROTACs is warranted for their clinical application in oncology.
