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

作者：Zhang Lei; Dewan Varun; Yin Hang

来源：Journal of Medicinal Chemistry, 2017, 60(12): 5029-5044.

DOI：10.1021/acs.jmedchem.7b00419

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-kappa B 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 it both vaccine adjuvants and anticancer therapies based on multi-TLR activation.

• 出版日期2017-6-22