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Design and optimisation of a small-molecule TLR2/4 antagonist for anti-tumour therapyElectronic supplementary information (ESI) available. See DOI: 10.1039/d1md00175b
- Source :
- MedChemComm; 2021, Vol. 12 Issue: 10 p1771-1779, 9p
- Publication Year :
- 2021
-
Abstract
- In anti-tumour therapy, the toll-like receptor 2/4 (TLR2/4) signalling pathway has been a double-edged sword. TLR2/4 agonists are commonly considered adjuvants for immune stimulation, whereas TLR2/4 antagonists demonstrate more feasibility for anti-tumour therapy under specific chronic inflammatory situations. In individuals with cancer retaliatory proliferation and metastasis after surgery, blocking the TLR2/4 signalling pathway may produce favourable prognosis for patients. Therefore, here, we developed a small-molecule co-inhibitor that targets the TLR2/4 signalling pathway. After high-throughput screening of a compound library containing 14 400 small molecules, followed by hit-to-lead structural optimisation, we finally obtained the compound TX-33, which has effective inhibitory properties against the TLR2/4 signalling pathways. This compound was found to significantly inhibit multiple pro-inflammatory cytokines released by RAW264.7 cells. This was followed by TX-33 demonstrating promising efficacy in subsequent anti-tumour experiments. The current results provide a novel understanding of the role of TLR2/4 in cancer and a novel strategy for anti-tumour therapy.
Details
- Language :
- English
- ISSN :
- 20402503 and 20402511
- Volume :
- 12
- Issue :
- 10
- Database :
- Supplemental Index
- Journal :
- MedChemComm
- Publication Type :
- Periodical
- Accession number :
- ejs58085708
- Full Text :
- https://doi.org/10.1039/d1md00175b