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

Abstract

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.

Recent clinical trends in Toll‐like receptor targeting therapeutics

“…The only known agonist for this TLR is poly‐ICLC (and its derivatives), which is being investigated in various clinical trials . The success and ubiquitous nature of poly‐ICLC led to the belief that this was the only realistic possibility for targeting this TLR; however, recent studies have identified other small molecules that can either inhibit or activate TLR3 . These alternatives will not be available for clinical trials for a considerable period of time.…”

New chimeric TLR7/NOD2 agonist is a potent adjuvant to induce mucosal immune responses

“…Recently, the cooperation between TLR7 and NOD2 signaling was demonstrated in response to Candida parapsilosis infection [19] . As part of the evaluation of the interest of the crosstalk between PRR agonists, the combination of multiple agonists in a single molecule showed promising effects in multiple studies [20] , [21] , [22] . Most pathogens enter the body through mucosa.…”

Radical Reactions for the Synthesis of 3‐Substituted Chroman‐4‐ones

“…Consequently, a plethora of synthetic methods has been developed for the preparation of those scaffolds in the past century (Scheme ) . Generally, the synthesis of chroman‐4‐ones could be achieved by intramolecular oxo‐Michael addition of 2'‐hydroxychalcone catalyzed by acids/bases (Scheme a), and condensation cyclization of o ‐hydroxyacetophenones with ketones or aldehydes (Scheme b) . However, those synthetic approaches only led to 2‐substituted and 2,2‐disubstituted chroman‐4‐ones.…”

“…[9] Generally, the synthesis of chroman-4-ones could be achieved by intramolecular oxo-Michael addition of 2′hydroxychalcone catalyzed by acids/bases (Scheme 2a), [10][11][12][13][14] and condensation cyclization of o-hydroxyacetophenones with ketones or aldehydes (Scheme 2b). [15][16][17][18] However, those synthetic approaches only led to 2-substituted and 2,2-disubstituted chroman-4-ones. For the synthesis of 3-substituted chroman-4-ones, intramolecular Stetter reaction of alkenyl aldehydes catalyzed by N-heterocyclic carbene (NHC) was found to be an efficient procedure (Scheme 2c).…”