CU-T12-9 is a small-molecule agonist that specifically targets the Toll-like receptor TLR1/TLR2 heterodimer, with an EC50 of 52.9nM. CU-T12-9 promotes the dimerization of TLR1 and TLR2, thereby activating the NF-κB signaling pathway[1-2]. CU-T12-9 is primarily used in research related to immune regulation, vaccine adjuvants, anti-tumor agents, and the development of therapeutics for inflammatory and infectious diseases[3-4].
In vitro, treatment of TREM1-knockdown human hepatocellular carcinoma Huh-7 and MHCC-97H cells with CU-T12-9 (1μM) activated the TLR2 signaling pathway and promoted the phosphorylation of PI3K-p85α and AKT, thereby rescuing the impairment in cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) caused by TREM1 downregulation[5]. Treatment of LPS (100ng/mL) and IFN-γ (10ng/mL)-induced M1-type bone marrow-derived macrophages with CU-T12-9 (1μM) for 2 hours reversed the inhibitory effect of photobiomodulation (PBM) on the TLR2/NLRP3/Caspase-1/IL-1β signaling pathway, significantly suppressed the expression of autophagy-related proteins LC3B and Beclin-1, and enhanced inflammasome activity and pro-inflammatory cytokine secretion[6].
In vivo, intramuscular injection of CU-T12-9 (10mg/kg) in a diabetic hindlimb ischemia mouse model twice a week for six weeks (total of six injections), specifically activated the NF-κB signaling pathway and significantly inhibited the formation of new blood vessels from endothelial cells and smooth muscle cells in the ischemic muscle tissue[7].
References:
[1] Cheng K, Gao M, Godfroy JI, et al. Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists. Sci Adv. 2015;1(3):e1400139.
[2] Wang Z, Zhu D, Yang F, et al. POSTN knockdown suppresses IL-1β-induced inflammation and apoptosis of nucleus pulposus cells via inhibiting the NF-κB pathway and alleviates intervertebral disc degeneration. J Cell Commun Signal. 2024 May 7;18(2):e12030.
[3] Chen Y, Guo Y, Song Z, et al. Luteolin restricts ASFV replication by regulating the NF-κB/STAT3/ATF6 signaling pathway. Vet Microbiol. 2022 Oct;273:109527.
[4] Zhang W, Liu W, Hu X. Robinin inhibits pancreatic cancer cell proliferation, EMT and inflammation via regulating TLR2-PI3k-AKT signaling pathway. Cancer Cell Int. 2023 Dec 18;23(1):328.
[5] Ren L, Qiao GL, Zhang SX, et al. Pharmacological Inhibition or Silencing of TREM1 Restrains HCC Cell Metastasis by Inactivating TLR/PI3K/AKT Signaling. Cell Biochem Biophys. 2024 Sep;82(3):2673-2685.
[6] Zuo X, Ju C, Zhang Z, et al. Photobiomodulation regulates inflammation and autophagy in spinal cord injury through NLRP3/Caspase-1/IL-1β pathway by targeting TLR2. Mol Immunol. 2025 Jun;182:1-10.
[7] Wang J, Zhang L, Duan W, et al. Salidroside analogue C-30 promotes neovascularization in diabetic hindlimb ischemic mice by inducing macrophage M2 polarization. Int Immunopharmacol. 2025 Oct 22;167:115708.
CU-T12-9是一种特异性Toll样受体TLR1/TLR2异二聚体的小分子激动剂，其EC50为52.9nM，CU-T12-9通过促进TLR1和TLR2二聚化，进而激活NF-κB信号通路[1-2]。CU-T12-9主要被用于免疫调节、疫苗佐剂、抗肿瘤制剂以及治疗炎症和传染病药物开发相关研究中[3-4]。
在体外，CU-T12-9（1μM）处理敲低TREM1的人肝癌Huh-7和MHCC-97H细胞，CU-T12-9激活了TLR2信号通路，促进PI3K-p85α和AKT的磷酸化水平，从而挽救了因TREM1下调导致的细胞增殖、侵袭和上皮-间质转化（EMT）过程受阻[5]。CU-T12-9（1μM）处理经LPS（100ng/mL）和IFN-γ（10ng/mL）诱导的M1型骨髓源性巨噬细胞2小时，CU-T12-9逆转了光生物调节（PBM）对TLR2/NLRP3/Caspase-1/IL-1β信号通路的抑制作用，并显著抑制自噬相关蛋白LC3B和Beclin-1的表达，同时增强炎症小体活性及促炎因子分泌[6]。
在体内，CU-T12-9（10mg/kg）肌肉注射处理糖尿病后肢缺血小鼠，每周两次，一共注射6周，通过特异性激活NF-κB信号通路，显著抑制缺血肌肉组织中内皮细胞和平滑肌细胞的新生血管形成[7]。