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

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.