Design, Synthesis, and Structure-Activity Relationship of N-Aryl-N'-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy.
Zhipeng ChenLina ZhangJunjie YangLu ZhengFanjie HuSiqin DuanKutty Selva NandakumarShu-Wen LiuHang YinKui ChengPublished in: Journal of medicinal chemistry (2021)
The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1β from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.
Keyphrases
- toll like receptor
- inflammatory response
- nuclear factor
- endothelial cells
- immune response
- highly efficient
- lps induced
- oxidative stress
- induced pluripotent stem cells
- cell cycle arrest
- healthcare
- pluripotent stem cells
- rheumatoid arthritis
- nk cells
- photodynamic therapy
- risk assessment
- squamous cell carcinoma
- climate change
- human health
- young adults
- papillary thyroid
- lymph node metastasis