2. Academic Validation
  3. Design, synthesis and anti-tumor evaluation of 1,2,4-triazol-3-one derivatives and pyridazinone derivatives as novel CXCR2 antagonists

Design, synthesis and anti-tumor evaluation of 1,2,4-triazol-3-one derivatives and pyridazinone derivatives as novel CXCR2 antagonists

  • Eur J Med Chem. 2021 Dec 15:226:113812. doi: 10.1016/j.ejmech.2021.113812.
Xun Zhang 1,  Jingyi Luo 1,  Qinyuan Li 2,  Qilei Xin 1,  Lizhen Ye 1,  Qingyun Zhu 3,  Zhichao Shi 1,  Feng Zhan 1,  Bizhu Chu 4,  Zijian Liu 5,  Yuyang Jiang 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China.
  • 2 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China.
  • 3 The First Affiliated Hospital, Department of Oncology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 4 School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, PR China.
  • 5 Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, 518057, PR China.
  • 6 Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 34536673 DOI: 10.1016/j.ejmech.2021.113812
Abstract

Chemokine Receptor 2 (CXCR2) is the receptor of glutamic acid-leucine-arginine sequence-contained chemokines CXCs (ELR+ CXCs). In recent years, CXCR2-target treatment strategy has come a long way in Cancer therapy. CXCR2 antagonists could block CXCLs/CXCR2 axis, and are widely used in regulating immune cell migration, tumor metastasis, Apoptosis and angiogenesis. Herein, two series of new CXCR2 small-molecule inhibitors, including 1,2,4-triazol-3-one derivatives 1-11 and pyridazinone derivatives 12-22 were designed and synthesized based on the proof-to-concept. The pyridazinone derivative 18 exhibited good CXCR2 antagonistic activity (69.4 ± 10.5 %Inh at 10 μM) and demonstrated its significant Anticancer metastasis activity in MDA-MB-231 cells and remarkable anti-angiogenesis activity in HUVECs. Furthermore, noteworthy was that 18 exhibited an obvious synergistic effect with Sorafenib in anti-proliferation assay in MDA-MB-231 cells. Moreover, 18 showed a distinct reduction of the phosphorylation levels of both PI3K and Akt proteins in MDA-MB-231 cells, and also affected the expression levels of Other PI3K/Akt signaling pathway-associated proteins. The molecular docking studies of 18 with CXCR2 also verified the rationality of our design strategy. All of these results revealed pyridazinone derivative 18 as a promising CXCR2 Antagonist for future Cancer therapy.

Keywords

1,2,4-Triazol-3-one; Antagonists; Anti-tumor; CXCR2; Pyridazinone; Triple-negative breast cancer.

Figures