Discovery of novel thiophene [2,3-D] pyrimidine–thiazole derivative as promising MNK inhibitor to treat breast cancer

• Published in: Journal of molecular structure Vol. 1321; p. 140125
• Main Authors: Zhu, Peng, Yang, You, Qian, Jianqiang, Han, Jun, Kong, Dairui, Sun, Bo, Zhang, Jian, Wei, Jingtao, Guo, Qulian, Nian, Sihui, Zhou, Lixiang, Wang, Guodong, Hou, Shaohua
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.02.2025
• Subjects: Antitumor activity; MNK inhibitor; Structural optimization; Thiophene [2,3-D] pyrimidine–thiazole derivatives; Virtual screening; Virtual screening; Antitumor activity; MNK inhibitor; Structural optimization; Thiophene [2,3-D] pyrimidine–thiazole derivatives
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140125

•4s, a promising MNKs inhibitor (MNK1/2 IC50 = 987/1048 nM) was discovered based on virtual screening•18 novel thiophene [2,3-D] pyrimidine–thiazole derivatives were designed and synthesized by structural optimization•Compound 5l exhibited the best inhibitory activity on MNKs (MNK1/2 IC50 = 23/62 nM)•5l exerted potent cytotoxic (IC50 = 0.8 µM) and inhibit cell migration, induced cell apoptosis, cell cycle arrest and mitochondrial dysfunction of MCF-7 Mitogen-activated protein kinase–interacting kinases (MNKs) play a key role in the occurrence and migration of tumors and have become promising targets for tumor therapy. Nevertheless, the development progress on the MNKs inhibitors against cancer was relatively slow. In this study, compound 4s (MNK1/2 half-maximal inhibitory concentration [IC50] = 987/1048 nM), a promising MNKs inhibitor was discovered based on virtual screening. After the structural optimization of compound 4s, 18 novel thiophene [2,3-D] pyrimidine–thiazole derivatives were designed and prepared, and their inhibitory effect on MNKs was determined. Among which, compound 5l exhibited the best inhibitory activity on MNKs (MNK1/2 IC50 = 23/62 nM) and relatively high selectivity among 125 kinases. Results from in vitro experiments indicated that compound 5l could significantly inhibit the in vitro proliferation (IC50 = 0.8 ± 0.1 μM) and migration of breast cancer cells, which demonstrated that compound 5l is a promising MNK inhibitor to treat breast cancer and need further study. [Display omitted]