2. Academic Validation
  3. Discovery of potent, selective human TLR1/2 agonists: N-quinoline-N'-(thiophen-2-yl)thiourea analogs for potential cancer immunotherapy

Discovery of potent, selective human TLR1/2 agonists: N-quinoline-N'-(thiophen-2-yl)thiourea analogs for potential cancer immunotherapy

  • Eur J Med Chem. 2025 Nov 5:297:117968. doi: 10.1016/j.ejmech.2025.117968.
Xiaoshan Zeng 1,  Qiuyue Fu 1,  Ruilian Liao 2,  Hua Mei 2,  Lan Huang 1,  Zhibo Zhu 3,  Kui Cheng 4,  Zhipeng Chen 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, Guangdong, China.
  • 3 Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, Guangdong, China. Electronic address: zhuzb676@smu.edu.cn.
  • 4 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: chengk@smu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: czpwyq@smu.edu.cn.
PMID: 40683144 DOI: 10.1016/j.ejmech.2025.117968
Abstract

TLR2 agonists represent promising Cancer immunotherapeutic due to their unique combination of potency and safety. SMU-C68, a human TLR1/2 specific small molecule agonist was identified, exhibiting a remarkable four-fold increase in biological activity compared to previously reported SMU-C80 with enhanced aqueous solubility. The cellular and protein level results confirmed that SMU-C68 facilitated the dimerization of TLR1 and TLR2 proteins, leading to the specific activation of TLR1/2 heterodimers. Upon activation, TLR2 recruited the adaptor protein MyD88, initiating downstream NF-κB signaling pathway. Moreover, treatment with SMU-C68 induced the release of pro-inflammatory factors, such as TNF-α and IL-1β, in human PBMC cells. Notably, SMU-C68 exhibited good selectivity towards human species and showed minimal effects on murine cells. Furthermore, in vitro co-culture experiments demonstrated that SMU-C68 exerted a positive influence on immune cell activation and tumor cell Apoptosis. These findings strongly emphasize the potential of SMU-C68 in modulating immune responses and eliciting anti-tumor activity.

Keywords

Cancer immunotherapy; TLR1/2 small molecule agonist; Toll-like receptor 2.

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