The Exploration of Indole-Based LSD1-Targeted Inhibitors for Enhanced Immune Response in Gastric Cancer via the PD-L1/PD‑1 Axis

Gastric cancer is one of the major health threats to
human beings
and has a low response rate to emerging immunotherapy. We herein reported
a novel indole-based LSD1-targeted antigastric agent 7ae, which was able to enhance the sensitivity of gastric cancer cells
to a T-cell-mediated immune response. It exhibited potent LSD1 inhibitory
activity (IC50 = 0.080 ± 0.002 μM) and reduced
the expression of PD-L1, which in turn promoted the T-cell killing
response in gastric cancer cells. As a result, 7ae acted
as an active LSD1 inhibitor, exerting excellent anti-invasion and
anti-migration effects in gastric cancer cells and leading to significant
suppression of the growth of xenograft gastric tumors without obvious
toxicity in vivo. Collectively, 7ae has
been demonstrated to be a novel, potent LSD1 inhibitor with the potential
to be used as an antigastric agent, as well as a useful tool compound
for exploratory studies of T-cell-mediated immunity and/or immunotherapy
in gastric cancer.