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  3. Discovery of benzofuran-2-carboxylic acid derivatives as lymphoid tyrosine phosphatase (LYP) inhibitors for cancer immunotherapy

Discovery of benzofuran-2-carboxylic acid derivatives as lymphoid tyrosine phosphatase (LYP) inhibitors for cancer immunotherapy

  • Eur J Med Chem. 2023 Oct 5;258:115599. doi: 10.1016/j.ejmech.2023.115599.
Xiao Liang 1,  Huajun Zhao 2,  Jintong Du 3,  Xue Li 4,  Kangshuai Li 5,  Zhongcheng Zhao 4,  Wenchao Bi 2,  Xiaotong Zhang 4,  Dian Yu 4,  Jian Zhang 2,  Hao Fang 4,  Xuben Hou 6
Affiliations

Affiliations

  • 1 Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China; Department of Pharmacy, Qilu Hospital of Shandong University, Ji'nan, Shandong, 250012, China.
  • 2 Institute of Immunopharmaceutical Sciences, and Key Laboratory of Chemical Biology of Natural Pro ducts (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China.
  • 3 Shandong Cancer Hospital and Institute, Shandong First Medical University, Jinan, Shandong, 250117, China.
  • 4 Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China.
  • 5 Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 6 Institute of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), Cheeloo College of Medicine, School of Pharmaeutical Science, Shandong University, Jinan, Shandong, 250012, China. Electronic address: [email protected].
PMID: 37399712 DOI: 10.1016/j.ejmech.2023.115599
Abstract

Lymphoid-tyrosine Phosphatase (LYP) is mainly expressed in the immune system and plays an important role in the T-cell receptor (TCR) signaling pathway and tumor immunity. Herein, we identify benzofuran-2-carboxylic acid as a potent pTyr mimic and design a new series of new LYP inhibitors. The most active compound, D34 and D14, reversibly inhibits LYP (Ki = 0.93 μM and 1.34 μM) and possess a certain degree of selectivity toward other phosphatases. Meanwhile, D34 and D14 regulate the TCR signaling by specifically inhibiting LYP. In particular, D34 and D14 significantly suppress tumor growth in an MC38 syngeneic mouse model by boosting antitumor immunity, including activation of T-cell and inhibition of M2 macrophage polarization. Moreover, treatment of D34 or D14 upregulate PD-1/PD-L1 expression, which can be leveraged with PD-1/PD-L1 inhibition to augment immunotherapy. In summary, our study demonstrates the feasibility of targeting LYP for Cancer Immunotherapy and provides new lead compounds for further drug development.

Keywords

Immunotherapy; LYP inhibitor; PD-1/PD-L1 blockade; PTPN22.

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