Design and optimisation of a small-molecule TLR2/4 antagonist for anti-tumour therapy. Issue 10 (7th September 2021)

• Record Type: Journal Article
• Authors: Xu, Qun; Li, Tian; Chen, Hekai; Kong, Jun; Zhang, Liwei; Yin, Hang
• Is Part Of: RSC medicinal chemistry. Volume 12:Issue 10(2021)
• Page Start: 1771
• Page End: 1779
• Publication Date: 2021-09-07
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d1md00175b
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : A novel anti-tumour strategy by optimising a promising molecule targeting the TLR2/4 pathway simultaneously, which inhibits proliferation of multiple cancer cells. 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.