A benzoxazole derivative PO‐296 inhibits T lymphocyte proliferation by the JAK3/STAT5 signal pathway

• Published in: Journal of cellular biochemistry Vol. 120; no. 6; pp. 9193 - 9202
• Main Authors: Luo, Xing‐yan, Zhou, Hong, Wang, Si‐yu, Xiong, Jing, Mo, Chun‐fen, Guo, Hui‐jie, Wang, Yan‐tang, Yang, Shu‐xia, Li, Li‐mei, Zou, Qiang, Liu, Yang
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2019
• Subjects: 1-Phosphatidylinositol 3-kinase; [2‐(6‐chlorobenzo[d]oxazol‐2‐yl)‐4,5,6,7‐tetrahydro‐2H‐indazol‐3‐ol] (PO‐296); AKT protein; Autoimmune diseases; CD69 antigen; Cytotoxicity; G1 phase; Immunosuppressive activity; Immunosuppressive agents; Interferon; Interleukins; Janus kinase; Janus kinase 3; Kinases; Lead compounds; Lymphocytes; Lymphocytes T; Medical treatment; Oxazol; Phosphorylation; Proteins; Stat5 protein; T lymphocyte proliferation; Toxicity; Transcription; [2-(6-chlorobenzo[d]oxazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol] (PO-296); Immunosuppressive activity; T lymphocyte proliferation
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.28195

Immunosuppressants have shown striking achievements in treating autoimmune diseases in recent years. It is urgent to develop more immunosuppressants to provide more options for patients. PO‐296 [2‐(6‐chlorobenzo[d]oxazol‐2‐yl)‐4,5,6,7‐tetrahydro‐2H‐indazol‐3‐ol] was identified as a novel benzoxazole derivative. We observed that it exhibits an obvious immunosuppressive activity to T lymphocytes. PO‐296 significantly inhibited the proliferation of activated human T lymphocyte without cytotoxicity. Moreover, PO‐296 did not affect the expression of cluster of differentiation (CD)‐25 or CD69 but induced T lymphocyte cycle arrest in the G0/G1 phase. Furthermore, PO‐296 inhibited interleukin (IL)‐6, IL‐17, and interferon gamma expression but had no effect on IL‐2, IL‐4, or IL‐10. Yet, importantly, PO‐296 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5), increased the phosphorylation of p70S6K, but did not affect the phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt)/mitogen‐activated protein kinase pathway. In conclusion, these findings indicate that PO‐296 inhibits human activated T‐lymphocyte proliferation by affecting the janus kinase 3 (JAK3)/STAT5 pathway. PO‐296 possesses a potential lead compound for the design and development of new immunosuppressants for the treatment of autoimmune diseases. The structure of [2‐(6‐chlorobenzo[d]oxazol‐2‐yl)‐4,5,6,7‐tetrahydro‐2H‐indazol‐3‐ol] (PO‐296) is completely different from the known immunosuppressants. This study identified that PO‐296 inhibits human activated T lymphocyte proliferation by affecting the JAK3/STAT5 pathway. PO‐296 possesses a potential lead compound for the design and development of new immunosuppressants for the treatment of autoimmune diseases.