Discovery of Small Molecules as Multi-Toll-like Receptor Agonists with Proinflammatory and Anticancer Activities

Therapies based on activation of
multiple Toll-like receptors (TLRs)
may offer superior therapeutic profiles than that of single TLR activation.
To discover new small molecules that could activate multiple TLRs,
we performed a cell-based high-throughput screening of a small-molecule
library based on TLR3-mediated NF-κB activation. Subsequent
structural optimization and counterscreening of other TLRs produced
the first small molecule 17e (CU-CPT17e)
capable of simultaneously activating TLRs 3, 8, and 9. Biochemical
studies demonstrated that 17e could induce a strong immune
response via the production of various cytokines in human monocytic
THP-1 cells. Furthermore, 17e inhibited the proliferation
of HeLa cancer cells by triggering apoptosis and arresting the cell
cycle at the S phase. These results showcase potential therapeutic
applications of 17e in both vaccine adjuvants and anticancer
therapies based on multi-TLR activation.