Details

Autor(en) / Beteiligte

• Qin, Mingze
• Meng, Yangyang
• Yang, Haoshen
• Liu, Lei
• Zhang, Haotian
• Wang, Simeng
• Liu, Chunyang
• Wu, Xia
• Wu, Di
• Tian, Ye
• Hou, Yunlei
• Zhao, Yanfang
• Liu, Yajing
• Xu, Congjun
• Wang, Lihui

Titel

Discovery of 4‑Arylindolines Containing a Thiazole Moiety as Potential Antitumor Agents Inhibiting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Ist Teil von

• Journal of medicinal chemistry, 2021-05, Vol.64 (9), p.5519-5534

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.