TC14012, a serum-stable derivative of T140, is a selective and peptidomimetic CXCR4 antagonist with an IC50 of 19.3 nM. TC14012 is a potent CXCR7 agonist with an EC50 of 350 nM for recruiting β-arrestin 2 to CXCR7. TC14012 has anti-HIV activity and anti-cancer activity [1-3].
TC14012(10-10-10-5M ; 37℃; 90 min) induce coupling of CXCR7 with β-arrestin in a dose-dependent manner in 293FT cell β-Arrestin recruitment assay[4]. In TC14012-treated(0-30µM) HUVECs(human umbilical vein endothelial cells), specific activation of CXCR7 significantly promoted the tubular formation of HUVECs[5]. TC14012 may promote osteogenesis or chondrodifferentiation in the treatment of mesenchymal stem cell (MSC) [6].
TC14012(10 mg/kg; i.p. ; 4 times every 6 days) significantly increased the left ventricular internal diameter-diastole/systole (LVID-d/s), a key cardiac structure index, and the EFFS, and left ventricular volume-diastole/systole (LV vol-d/s) in AMI mice. TC14012 reduced the infarct size and increased the vascular density in AMI model mice. TC14012 promoted angiogenesis in vivo, and TC14012 increased the levels of VWF, VEGFR2, p-SRC and p-PLC-γ as well as the p-P38/t-P38 ratio [7].
References:
[1]. Tamamura H, Omagari A, et,al. Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140. Bioorg Med Chem Lett. 2001 Jul 23;11(14):1897-902. doi: 10.1016/s0960-894x(01)00323-7. PMID: 11459656.
[2]. Gravel S, Malouf C, et,al. The peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: roles of receptor domains. J Biol Chem. 2010 Dec 3;285(49):37939-43. doi: 10.1074/jbc.C110.147470. Epub 2010 Oct 18. PMID: 20956518; PMCID: PMC2992227.
[3]. Gravel S, Malouf C, et,al. The peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: roles of receptor domains. J Biol Chem. 2010 Dec 3;285(49):37939-43. doi: 10.1074/jbc.C110.147470. Epub 2010 Oct 18. PMID: 20956518; PMCID: PMC2992227.
[4]. Ishizuka M, Harada M, et,al. CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor. Sci Rep. 2021 Feb 9;11(1):3426. doi: 10.1038/s41598-021-83022-5. Erratum in: Sci Rep. 2021 Jun 7;11(1):12340. PMID: 33564089; PMCID: PMC7873251.
[5]. Zhang M, Qiu L, et,al. CXCL12 enhances angiogenesis through CXCR7 activation in human umbilical vein endothelial cells. Sci Rep. 2017 Aug 15;7(1):8289. doi: 10.1038/s41598-017-08840-y. PMID: 28811579; PMCID: PMC5557870.
[6]. Wei ST, Huang YC, et,al. Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation. Stem Cell Res Ther. 2021 May 29;12(1):314. doi: 10.1186/s13287-021-02402-w. PMID: 34051857; PMCID: PMC8164772.
[7]. Zhang S, Yue J, et,al. Activation of CXCR7 alleviates cardiac insufficiency after myocardial infarction by promoting angiogenesis and reducing apoptosis. Biomed Pharmacother. 2020 Jul;127:110168. doi: 10.1016/j.biopha.2020.110168. Epub 2020 Apr 28. PMID: 32361166.
TC14012 是 T140 的血清稳定衍生物,是一种选择性的 CXCR4 拮抗剂,IC50 为 19.3 nM。TC14012 是有效的 CXCR7 激动剂,可将 β-arrestin2 募集到 CXCR7,EC50 为 350 nM。TC14012 具有抗 HIV 活性和抗癌活性[1-3]。
293FT细胞中,TC14012(10-10-10-5M ; 37℃; 90分钟)以剂量依赖的方式诱导CXCR7与β-抑制素偶联[4]。在TC14012处理的(0-30µM) HUVECs中,CXCR7的特异性激活显著促进了HUVECs管状形成[5]。用TC14012处理MSCs,可能促进成骨或软骨分化[6]。
TC14012(10 mg/kg; i.p. ;每6 天 4次)显著提高AMI小鼠心脏结构指标左室内径-舒张/收缩压、EFFS和左室容积-舒张/收缩压。TC14012可减少AMI模型小鼠的心梗死面积,增加血管密度。TC14012促进体内血管生成,升高VWF、VEGFR2、p-SRC、p-PLC-γ水平及p-P38/t-P38比值[7]。