AC-73
目录号 : GC60550
AC-73是ClusterofDifferentiation147(CD147)的第一种特定的口服生物利用的抑制剂，可特异性破坏CD147的二聚化(结合位点在CD147的N端IgC2域中包括Glu64和Glu73)，从而抑制CD147/ERK1/2/STAT3/MMP-2途径，并抑制肝癌细胞的运动和侵袭。AC-73还是一种抗增殖药，也是白血病细胞自噬的诱导剂。
Cas No.:775294-71-8
Sample solution is provided at 25 µL, 10mM.
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- Purity: >99.50%
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AC-73 is a first specific, orally active inhibitor of cluster of differentiation 147 (CD147), which specifically disrupts CD147 dimerization, thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways. AC-73 inhibits the motility and invasion of hepatocellular carcinoma cells[1]. AC-73 is also an anti-proliferative drug and an inducer of autophagy in leukemic cells[2].
AC-73 (5-10 μM; 24 hours; SMMC-7721 and Huh-7 cells) treatment significantly decreases the migration ability of SMMC-7721 and Huh-7 cells in a dose-dependent manner and decreases the invasion of two HCC cells in a dose-dependent manner at 24 hours. AC-73 treatment reduces HCC metastases. There are no obvious effects on cell viability when two HCC cells are treated with AC-73 at a maximum concentration of 20 μM. The possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147[1]. AC-73 (5-10 μM; 24 hours; SMMC-7721 cells) treatment could significantly inhibit both MMP-2 and MMP-9 mRNA expression at the concentration of 10 μM, especially MMP-2, but no obvious effect on MMP-1, MMP-3, MMP-7, MMP-11 nor MMP-13. AC-73 could dose dependently reduce the expression of MMP-2 mRNA level and secretion of the protein level using RT-qPCR analysis and gelatin zymography experiments[1].AC-73 (5-20 μM; 6 hours; SMMC-7721 cells) treatment dose-dependently suppresses the phosphorylation of ERK1/2 and STAT3[1]. RT-PCR[1] Cell Line: SMMC-7721 cells
AC-73 (25-50 mg/kg; for 4 weeks; Male BALB/c nu/nu mice) treatment significantly decreases the incidence of metastatic foci in nude mice. AC-73 inhibits the phosphorylation of ERK1/2 and STAT3 in a dose-dependent manner. MMP-2 is also reduced by AC-73. AC-73 could not inhibit tumor cell proliferation in vivo[1]. Animal Model: Male BALB/c nu/nu mice (4-6 weeks) with SMMC-7721 cells[1]
[1]. Fu ZG, et al. A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells. Oncotarget. 2016 Feb 23;7(8):9429-47. [2]. Spinello I, et al. The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells. Haematologica. 2019 May;104(5):973-985.
| Cas No. | 775294-71-8 | SDF | |
| Canonical SMILES | OC(CNCC1=CC=C(C2=CC=CC=C2)C=C1)C3=CC=CC(O)=C3 | ||
| 分子式 | C21H21NO2 | 分子量 | 319.4 |
| 溶解度 | DMSO: ≥ 250 mg/mL (782.72 mM) | 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 | 3.1309 mL | 15.6544 mL | 31.3087 mL |
| 5 mM | 0.6262 mL | 3.1309 mL | 6.2617 mL |
| 10 mM | 0.3131 mL | 1.5654 mL | 3.1309 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。
CD147 Targeting by AC-73 Induces Autophagy and Reduces Intestinal Fibrosis Associated with TNBS Chronic Colitis
J Crohns Colitis 2022 Nov 23;16(11):1751-1761.PMID:35833587DOI:10.1093/ecco-jcc/jjac084.
Background and aims: Intestinal fibrosis is a common complication of inflammatory bowel diseases. Medical treatment of intestinal fibrosis is an unmet therapeutic need. CD147 overexpression can induce myofibroblast differentiation associated with extracellular matrix deposition, favouring the development of fibrosis. To understand whether CD147 may promote intestinal fibrosis, we analysed its expression and blocked its function by using its specific inhibitor AC-73 [3-{2-[([1,1'-biphenyl]-4-ylmethyl) amino]-1-hydroxyethyl} phenol] in the murine TNBS [trinitrobenzenesulfonic acid]-chronic colitis model associated with intestinal fibrosis. Methods: TNBS chronic colitis was induced by weekly intrarectal administration of escalating doses of TNBS. Ethanol-treated and untreated mice were used as controls. Separated groups of TNBS, ethanol-treated or untreated mice received AC-73 or vehicle administered intraperitoneally from day 21 to day 49. At day 49, mice were killed, and colons collected for histological analysis, protein and RNA extraction. CD147, α-SMA and activated TGF-β1 protein levels, CD147/ERK/STAT3 signalling pathway and autophagy were assessed by Western blot, collagen and inflammatory/fibrogenic cytokines mRNA tissue content by quantitative PCR. Results: In mice with chronic TNBS colitis, CD147 protein level increased during fibrosis development in colonic tissue, as compared to control mice. CD147 inhibition by AC-73 treatment reduced intestinal fibrosis, collagen and cytokine mRNA tissue content, without significant modulation of activated TGF-β1 protein tissue content. AC-73 inhibited CD147/ERK1/2 and STAT3 signalling pathway activation and induced autophagy. Conclusions: CD147 is a potential new target for controlling intestinal fibrosis and its inhibitor, AC-73, might represent a potential new anti-fibrotic therapeutic option in IBD.
The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells
Haematologica 2019 May;104(5):973-985.PMID:30467201DOI:10.3324/haematol.2018.199661.
CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 represents a new hematologic target and whether its inhibitor AC-73 may be used in leukemia therapy may reveal an alternative treatment strategy in patients with acute myeloid leukemia (AML). We analyzed CD147 expression and function in hematopoietic progenitor cells from normal cord blood, in several leukemic cell lines and in primary leukemic blasts obtained from patients with AML. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. We demonstrated that CD147 overexpression promotes leukemic cell proliferation. We showed that AC-73 exhibits a potent growth inhibitory activity in leukemic cells, by inhibiting the ERK/STAT3 activation pathway and activating autophagy. We demonstrated that AC-73 exerts an anti-proliferative effect additive to chemotherapy by enhancing leukemic cell sensitivity to Ara-C-induced cytotoxicity or to ATO-induced autophagy. We also reported CD147 expression in the fraction of leukemic blasts expressing CD371, a marker of leukemic stem cells. Altogether, our study indicates CD147 as a novel potential target in the treatment of AML and AC-73 as an anti-proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeutic agents.
A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells
Oncotarget 2016 Feb 23;7(8):9429-47.PMID:26882566DOI:10.18632/oncotarget.6990.
CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression.
Synthesis and Evaluation of a Novel Small-molecule Compound as an Anticancer Inhibitor of CD147
Biomed Environ Sci 2019 Sep;32(9):673-686.PMID:31635683DOI:10.3967/bes2019.086.
Objective: Cancer is a serious threat to human health. Despite extensive research on cancer treatment, there is a growing demand for new therapies. CD147 is widely involved in tumor development, but it is unclear whether cancer cell malignancy is affected by CD147 expression level. The first compound (AC-73) targeting CD147 could only act on advanced tumors and inhibit metastasis. Therefore, new compounds with better anticancer activity should be explored. Methods: Wst-1 assays were used to confirm the effect of novel compounds on proliferation. Apoptosis tests were used to evaluate their proapoptotic capacity. A nude mouse model was used to demonstrate in vivo anticancer activity and safety of the compounds. Western blots were used to suggest a molecule mechanism. Results: There is a positive correlation between CD147 expression and tumor cell proliferation. A new compound, HA-08, was synthesized and proved to be more active than AC-73. HA-08 could inhibit cancer cell viability and promote cancer cell apoptosis both in vitro and in vivo. HA-08 induces cancer apoptosis, mainly by disrupting the CD147-CD44 interaction and then down-regulating the JAK/STAT3/Bcl-2 signaling pathway. Conclusion: Our results have clarified the tumor specificity of CD147 and its drug target characteristics. The biological profile of HA-08 suggests that this compound could be developed as a potential anticancer agent.