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Design and Synthesis of 3-(2H-Chromen-3-yl)-5-aryl-1,2,4-oxadiazole Derivatives as Novel Toll-like Receptor 2/1 Agonists That Inhibit Lung Cancer In Vitro and In Vivo.
Wang, Yijie; Cheng, Xu; Liu, Xinru; Xu, Jing; Wang, Lin; Zhang, Shouguo; Liu, Shuchen; Peng, Tao.
Afiliação
  • Wang Y; Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P. R. China.
  • Cheng X; Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P. R. China.
  • Liu X; Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P. R. China.
  • Xu J; Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P. R. China.
  • Wang L; Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P. R. China.
  • Zhang S; Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P. R. China.
  • Liu S; Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P. R. China.
  • Peng T; Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P. R. China.
J Med Chem ; 67(6): 4583-4602, 2024 Mar 28.
Article em En | MEDLINE | ID: mdl-38498304
ABSTRACT
Toll-like receptor (TLR) 2 is a transmembrane receptor that participates in the innate immune response by forming a heterodimer with TLR1 or TLR6. TLR2 agonists play an important role in tumor therapy. Herein, we synthesized a series of 3-(2H-chromen-3-yl)-5-aryl-1,2,4-oxadiazole derivatives and identified WYJ-2 as a potent small and selective molecule agonist of TLR2/1, with an EC50 of 18.57 ± 0.98 nM in human TLR2 and TLR1 transient-cotransfected HEK 293T cells. WYJ-2 promoted the formation of TLR2/1 heterodimers and activated the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, our study indicated that WYJ-2 could induce pyroptosis in cancer cells, mediated by activating the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. WYJ-2 exhibited effective anti-non-small cell lung cancer (NSCLC) activity in vitro and in vivo. The discovery that activating TLR2/1 induces pyroptosis in cancer cells may highlight the prospects of TLR2/1 agonists in cancer treatment in the future.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptor 2 Toll-Like / Neoplasias Pulmonares Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptor 2 Toll-Like / Neoplasias Pulmonares Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article