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Design, Synthesis, ...
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
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- Chen, Zhipeng (författare)
- Southern Medical University, Guangzhou, China
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- Zhang, Lina (författare)
- Southern Medical University, Guangzhou China
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- Yang, Junjie (författare)
- Southern Medical University, Guangzhou, China
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- Zheng, Lu (författare)
- Southern Medical University, Guangzhou, China
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- Hu, Fanjie (författare)
- Southern Medical University, Guangzhou, China
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- Duan, Siqin (författare)
- Southern Medical University, Guangzhou, China
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- Nandakumar, Kutty Selva, 1965- (författare)
- Southern Medical University, Guangzhou, China
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- Liu, Shuwen (författare)
- Southern Medical University, Guangzhou, China
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- Yin, Hang (författare)
- Tsinghua University, Beijing, China
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- Cheng, Kui (författare)
- Southern Medical University, Guangzhou, China
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(creator_code:org_t)
- 2021-05-24
- 2021
- Engelska.
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Ingår i: Journal of Medicinal Chemistry. - Washington, DC : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:11, s. 7371-7389
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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. © 2021 American Chemical Society
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- small-molecule inhibitors
- discovery
- recognition
- receptors
- immunity
- cells
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Chen, Zhipeng
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Zhang, Lina
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Yang, Junjie
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Zheng, Lu
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Hu, Fanjie
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Duan, Siqin
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Nandakumar, Kutt ...
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Liu, Shuwen
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Yin, Hang
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Cheng, Kui
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