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

Abstract

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 <b>A30</b> exhibited outstanding biochemical activity, with an IC₅₀ of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, <b>A30</b> significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, <b>A30</b> showed favorable <i>in vivo</i> antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, <b>A30</b> 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 <b>A30</b> inhibited tumor growth by activating the immune microenvironment. We concluded that <b>A30</b> is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.