IT1t
目录号 : GC36350
A CXCR4 antagonist
Cas No.:864677-55-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
IT1t is a chemokine (C-X-C motif) receptor 4 (CXCR4) antagonist (IC50s = 8 and 11 nM for the human and rat receptors, respectively).1 It is selective for CXCR4 over human ether-a-go-go-related gene potassium channels (hERG/Kv11.1; IC50 = 13,240 nM). IT1t inhibits calcium mobilization induced by chemokine (C-X-C-motif) ligand 12 (CXCL12) in CEM cells (IC50 = 1.1 nM) and decreases CXCL12-induced migration of Jurkat cells (IC50 = 79.1 nM).1,2 It inhibits replication of the HIV-1 strain NL4-3 in MT-4 cells and isolated human peripheral blood mononuclear cells (PBMCs) stimulated with phytohemagglutinin (PHA; IC50s = 14.2 and 19 nM, respectively).2 IT1t (20 ?M) reduces tumor growth in an MDA-MB-231-B zebrafish xenograft model.3
1.Thoma, G., Streiff, M.B., Kovarik, J., et al.Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivoJ. Med. Chem.51(24)7915-7920(2008) 2.Van Hout, A., D'huys, T., Oeyen, M., et al.Comparison of cell-based assays for the identification and evauation of competitive CXCR4 inhibitorsPLoS One12(4)e0176057(2017) 3.Tulotta, C., Stefanescu, C., Beletkaia, E., et al.Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft modelDis. Model Mech.9(2)141-153(2016)
| Cas No. | 864677-55-4 | SDF | |
| Canonical SMILES | CC1(C)CN2C(CS/C(NC3CCCCC3)=N\C4CCCCC4)=CSC2=N1 | ||
| 分子式 | C21H34N4S2 | 分子量 | 406.65 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4591 mL | 12.2956 mL | 24.5912 mL |
| 5 mM | 0.4918 mL | 2.4591 mL | 4.9182 mL |
| 10 mM | 0.2459 mL | 1.2296 mL | 2.4591 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists
Science 2010 Nov 19;330(6007):1066-71.PMID:20929726DOI:10.1126/science.1194396.
Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein-coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120.
Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t
J Biol Chem 2021 Jan-Jun;296:100139.PMID:33268380DOI:10.1074/jbc.RA120.016612.
CXCR4, a member of the family of chemokine-activated G protein-coupled receptors, is widely expressed in immune response cells. It is involved in both cancer development and progression as well as viral infection, notably by HIV-1. A variety of methods, including structural information, have suggested that the receptor may exist as a dimer or an oligomer. However, the mechanistic details surrounding receptor oligomerization and its potential dynamic regulation remain unclear. Using both biochemical and biophysical means, we confirm that CXCR4 can exist as a mixture of monomers, dimers, and higher-order oligomers in cell membranes and show that oligomeric structure becomes more complex as receptor expression levels increase. Mutations of CXCR4 residues located at a putative dimerization interface result in monomerization of the receptor. Additionally, binding of the CXCR4 antagonist IT1t-a small drug-like isothiourea derivative-rapidly destabilizes the oligomeric structure, whereas AMD3100, another well-characterized CXCR4 antagonist, does not. Although a mutation that regulates constitutive activity of CXCR4 also results in monomerization of the receptor, binding of IT1t to this variant promotes receptor dimerization. These results provide novel insights into the basal organization of CXCR4 and how antagonist ligands of different chemotypes differentially regulate its oligomerization state.
Design, synthesis, and biological evaluation of CXCR4 ligands
Org Biomol Chem 2016 Nov 2;14(43):10298-10311.PMID:27752700DOI:10.1039/c6ob01484d.
A combination of the CXCR4 inverse agonist T140 with N-terminal CXCL12 oligopeptides has produced the first nanomolar synthetic CXCR4 agonists. In these agonists, the inverse agonistic portion provides affinity whereas the N-terminal CXCL12 sequence induces receptor activation. Several CXCR4 crystal structures exist with either CVX15, an inverse agonist closely related to T140 and IT1t, a small molecule; we therefore attempted to produce another CXCL12 oligopeptide combination with IT1t. For this purpose, a primary amino group was introduced by total synthesis into one of the methyl groups of IT1t, serving as an anchoring point for the oligopeptide graft. The introduction of the oligopeptides on this analog however yielded antagonists, one compound displaying high affinity. On the other hand, the amino-substituted analogue itself proved to be an inverse agonist with a binding affinity of 2.6 nM compared to 11.5 nM for IT1t. This IT1t-like analog is hitherto one of the most potent non-peptidic CXCR4 inverse agonists reported.
Progress toward rationally designed small-molecule peptide and peptidomimetic CXCR4 antagonists
Future Med Chem 2015;7(10):1261-83.PMID:26144264DOI:10.4155/fmc.15.64.
Over the last 5 years, X-ray structures of CXCR4 in complex with three different ligands (the small-molecule antagonist IT1t, the polypeptide antagonist CVX15 and the viral chemokine antagonist vMIP-II) have been released. In addition to the inherent scientific value of these specific X-ray structures, they provide a reliable structural foundation for studies of the molecular interactions between CXCR4 and its key peptide ligands (CXCL12 and HIV-1 gp120), and serve as valuable templates for further development of small-molecule CXCR4 antagonists with therapeutic potential. We here review recent computational studies of the molecular interactions between CXCR4 and its peptide ligands - based on the X-ray structures of CXCR4 - and the current status of small-molecule peptide and peptidomimetic CXCR4 antagonists.
Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model
Dis Model Mech 2016 Feb;9(2):141-53.PMID:26744352DOI:10.1242/dmm.023275.
Triple-negative breast cancer (TNBC) is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.