2. Academic Validation
  3. Development of an Imidazopyridazine-Based MNK1/2 Inhibitor for the Treatment of Lymphoma

Development of an Imidazopyridazine-Based MNK1/2 Inhibitor for the Treatment of Lymphoma

  • J Med Chem. 2024 Apr 11;67(7):5437-5457. doi: 10.1021/acs.jmedchem.3c02008.
Xinrui Yuan 1 2,  Dezhong Guan 3,  Chao Chen 1,  Shi Guo 1,  Hanshu Wu 3,  Hong Bu 1,  Chao-Yie Yang 2,  Mian Wang 4,  Jinpei Zhou 3,  Huibin Zhang 1
Affiliations

Affiliations

  • 1 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. China.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38103, United States.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. China.
  • 4 College of Life Science and Technology, Guangxi University, Nanning 530004, P. R. China.
PMID: 38564512 DOI: 10.1021/acs.jmedchem.3c02008
Abstract

The mitogen-activated protein kinase-interacting protein kinases (MNKs) are the only kinases known to phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at Ser209, which plays a significant role in cap-dependent translation. Dysregulation of the MNK/eIF4E axis has been found in various solid tumors and hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). Herein, structure-activity relationship studies and docking models determined that 20j exhibits excellent MNK1/2 inhibitory activity, stability, and hERG safety. 20j exhibits strong and broad antiproliferative activity against different Cancer cell lines, especially GCB-DLBCL DOHH2. 20j suppresses the phosphorylation of eIF4E in Hela cells (IC50 = 90.5 nM) and downregulates the phosphorylation of eIF4E and 4E-BP1 in A549 cells. In vivo studies first revealed that ibrutinib enhances the antitumor effect of 20j without side effects in a DOHH2 xenograft model. This study provided a solid foundation for the future development of a MNK Inhibitor for GCB-DLBCL treatment.

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