PRI-724
(Synonyms: Foscenvivint) 目录号 : GC61205
PRI-724（C-82前药，ICG-001类似物）是首创的Wnt信号调节剂，可抑制cAMP反应元件（CREB）结合蛋白和β连环蛋白（β-catenin）相互作用。
Cas No.:1422253-38-0
Sample solution is provided at 25 µL, 10mM.
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PRI-724 (C-82 prodrug, ICG-001 analog) is a first-in-class Wnt signaling modulator that inhibits the interaction between cAMP response element (CREB) binding protein and β-catenin[1]. The Wnt signaling pathway is a complex protein action network, whose functions are most commonly seen in embryonic development and cancer, but also involved in normal physiological processes in adult animals[2]. PRI-724 has anti-tumor and anti-fibrotic activities[3, 4].
In vitro, PRI-724 (25μM) treatment of human osteosarcoma cell line (SJSA-1 cells) for 24h significantly inhibited cell migration and invasion, and reduced the expression level of G1/S-specific cyclin D1 (Cyclind1)[5]. PRI-724 (0-40μM) treated head and neck squamous cell carcinoma (HNSCC) cell lines (Cal 27 and FADU cells) and significantly inhibited cell growth, with IC50 values of 8.3μM and 14.6μM for Cal 27 and FADU cells, respectively[6].
In vivo, PRI-724 (10mg/kg) was subcutaneously implanted via osmotic minipumps to treat mice with bleomycin-induced pulmonary fibrosis, which improved lung fibrosis, reduced the number of alveolar macrophages, and decreased the level of TGF-β1 in bronchoalveolar fluid (BALF)[7].
References:
[1] El-Khoueiry A B, Ning Y, Yang D, et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors[J]. 2013.
[2] Anastas J N, Moon R T. WNT signalling pathways as therapeutic targets in cancer[J]. Nature Reviews Cancer, 2013, 13(1): 11-26.
[3] Gabata R, Harada K, Mizutani Y, et al. Anti-tumor activity of the small molecule inhibitor PRI-724 against β-catenin-activated hepatocellular carcinoma[J]. Anticancer research, 2020, 40(9): 5211-5219.
[4] Osawa Y, Oboki K, Imamura J, et al. Inhibition of cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB)-binding protein (CBP)/β-catenin reduces liver fibrosis in mice[J]. EBioMedicine, 2015, 2(11): 1751-1758.
[5] Fang F, VanCleave A, Helmuth R, et al. Targeting the Wnt/β-catenin pathway in human osteosarcoma cells[J]. Oncotarget, 2018, 9(95): 36780.
[6] Kleszcz R, Frąckowiak M, Dorna D, et al. Combinations of PRI-724 Wnt/β-Catenin Pathway Inhibitor with Vismodegib, Erlotinib, or HS-173 Synergistically Inhibit Head and Neck Squamous Cancer Cells[J]. International Journal of Molecular Sciences, 2023, 24(13): 10448.
[7] Okazaki H, Sato S, Koyama K, et al. The novel inhibitor PRI-724 for Wnt/β-catenin/CBP signaling ameliorates bleomycin-induced pulmonary fibrosis in mice[J]. Experimental lung research, 2019, 45(7): 188-199.
PRI-724（C-82前药，ICG-001类似物）是首创的Wnt信号调节剂，可抑制cAMP反应元件（CREB）结合蛋白和β连环蛋白（β-catenin）相互作用[1]。Wnt信号通路是一个复杂的蛋白质作用网络，其功能最常见于胚胎发育和癌症，但也参与成年动物的正常生理过程[2]。PRI-724具有抗肿瘤、抗纤维化活性[3, 4]。
在体外，PRI-724（25μM）处理人类骨肉瘤细胞系（SJSA-1细胞）24h，显著抑制了细胞迁移和侵袭，降低了G1/S-特异性周期蛋白-D1（Cyclind1）的表达水平[5]。PRI-724（0-40μM）处理头部和颈部鳞状癌（HNSCC）细胞系（Cal 27和FADU细胞），显著抑制了细胞生长，对Cal 27和FADU细胞的IC50值分别为8.3μM和14.6μM[6]。
在体内，PRI-724（10mg/kg）通过渗透微型泵皮下植入治疗博来霉素（Bleomycin）诱导的肺纤维化小鼠，改善了小鼠的肺纤维化，减少了肺泡巨噬细胞数量，降低了支气管肺泡液（BALF）中TGF-β1水平[7]。
| Cell experiment [1]: | |
Cell lines | SJSA-1 cells |
Preparation Method | The in vitro migration and invasion assays were carried out using the 8μm pore-sized Transwell chamber system. Prior to loading the cells into the upper chamber, the lower chamber was filled with medium containing 10% FBS with 25μM PRI-724 or DMSO. Cells were starved overnight and added to serum-free medium containing 25μM PRI-724 or DMSO in the upper chamber at a concentration of 4×104 cells per well. For invasion assays, membranes were coated with a layer of 0.2mg/mL Matrigel. After incubation for 24h, the cells on the upper surface of the well were removed completely by a Q-tip. The wells were fixed in 10% formalin and stained with Crystal violet. The plate with inserts were then imaged with an upright microscope and the relative number of cells that migrated through the Transwell pores was quantified using NIH ImageJ. |
Reaction Conditions | 25μM; 24h |
Applications | PRI-724 significantly suppressed SJSA-1 cell migration by about 40% and invasion by about 30%, compared to control levels. |
| Animal experiment [2]: | |
Animal models | C57BL/6 mice |
Preparation Method | Bleomycin sulfate (mixture) was dissolved in sterile saline and injected via oropharyngeal aspiration at a dose of 1.25mg/kg of Bleomycin in a total volume of 50mL of saline. During the injection process, mice were anesthetized with 2.5% isoflurane delivered in a box. Mice were sus penned vertically on a stand for oropharyngeal aspiration. Osmotic minipumps containing PBS or 1 or 10mg/kg/day of PRI-724 were implanted subcutaneously. Alveolar macrophage isolation BAL was conducted for mice treated by Bleomycin 7 days after administration. BAL fluid (BALF) was collected on days 28 and 35 after Bleomycin injection, and centrifuged at 1000rpm for 10min. |
Dosage form | 10mg/kg; s.c. |
Applications | The administration of PRI-724 ameliorated pulmonary fibrosis induced by Bleomycin in mice when administered with a late, but not an early, treatment schedule. Analysis of bronchoalveolar fluid (BALF) showed a decreased number of alveolar macrophages. In addition, the level of TGF-β1 in BALF was decreased in mice treated with PRI-724. PRI-724 also inhibited the production of TGF-β1 by alveolar macrophages. |
References: | |
| Cas No. | 1422253-38-0 | SDF | |
| 别名 | Foscenvivint | ||
| Canonical SMILES | O=C(N([C@]([C@H](C)N1CC2=C3N=CC=CC3=CC=C2)([H])N4[C@@H](CC5=CC=C(OP(O)(O)=O)C=C5)C1=O)N(C)CC4=O)NCC6=CC=CC=C6 | ||
| 分子式 | C33H35N6O7P | 分子量 | 658.64 |
| 溶解度 | 储存条件 | 4°C, protect from light | |
| 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 | 1.5183 mL | 7.5914 mL | 15.1828 mL |
| 5 mM | 0.3037 mL | 1.5183 mL | 3.0366 mL |
| 10 mM | 0.1518 mL | 0.7591 mL | 1.5183 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。
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