APG-1387
目录号 : GC62640
APG-1387 是一种二价 SMAC 模拟物，是 IAP 拮抗剂，可阻断 IAP 家族蛋白 (XIAP，cIAP-1，cIAP-2 和 ML-IAP) 的活性。APG-1387 诱导 cIAP-1 和 XIAP 蛋白降解以及 caspase-3 激活和 PARP 裂解，从而导致细胞凋亡。APG-1387 可用于肝细胞癌，卵巢癌和鼻咽癌的研究。
Cas No.:1570231-89-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
APG-1387, a bivalent SMAC mimetic and an IAP antagonist, blocks the activity of IAPs family proteins (XIAP, cIAP-1, cIAP-2, and ML-IAP). APG-1387 induces degradation of cIAP-1 and XIAP proteins, as well as caspase-3 activation and PARP cleavage, which leads to apoptosis. APG-1387 can be used for the research of hepatocellular carcinoma, ovarian cancer, and nasopharyngeal carcinoma[1][2][3][4][5].
APG-1387 (0.02-20 μM; 24 h) induces rapid degradation of cIAPs in HepG2 and HCCLM3 cells[1].APG-1387 (2 μM; 24 h) enhances TNF-α- and TRAIL-mediated anti-cancer activities in HepG2 and HCCLM3 cells. APG-1387 sensitizes HepG2 and HCCLM3 cells to NK cell-mediated killing in vitro[1].
APG-1387 (20 mg/kg; i.p. every 3 days for 4 weeks) sensitizes HCCLM3 tumors toward NK cell-mediated killing in mice[1].APG-1387 (20 mg/kg; i.p. every 3 days for 4 weeks) monotherapy exhibits some degree of anti-tumor effect and is well tolerated in mice[1].
[1]. Chen Z, et, al. The SMAC Mimetic APG-1387 Sensitizes Immune-Mediated Cell Apoptosis in Hepatocellular Carcinoma. Front Pharmacol. 2018 Nov 6; 9:1298.
[2]. Li BX, et, al. Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway. J Exp Clin Cancer Res. 2018 Mar 12;37(1):53.
[3]. Li N, et, al. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis. Cancer Lett. 2016 Oct 10;381(1):14-22.
[4]. Li Q, et, al. Abstract 6216: Therapeutic potential of IAP inhibitor APG-1387 in combination with PARP- or MEK-targeted therapy, or chemotherapy in pancreatic cancer. American Association for Cancer Research. Aug 2020. 80(16).
[5]. Pan w, et, al. Abstract 1754: Smac mimetics APG-1387 synergizes with immune checkpoint inhibitors in preclinical models. American Association for Cancer Research. Jul 2018. 78(13).
| Cas No. | 1570231-89-8 | SDF | |
| 分子式 | C60H72N10O10S2 | 分子量 | 1157.4 |
| 溶解度 | DMSO : 50 mg/mL (43.20 mM; Need ultrasonic)|Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C, stored under nitrogen |
| 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 | 0.864 mL | 4.32 mL | 8.6401 mL |
| 5 mM | 0.1728 mL | 0.864 mL | 1.728 mL |
| 10 mM | 0.0864 mL | 0.432 mL | 0.864 mL |
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| 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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，
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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。
The SMAC Mimetic APG-1387 Sensitizes Immune-Mediated Cell Apoptosis in Hepatocellular Carcinoma
Front Pharmacol 2018 Nov 6;9:1298.PMID:30459627DOI:10.3389/fphar.2018.01298.
The inhibitor of apoptosis protein (IAP) genes are frequently overexpressed in malignancies. Second mitochondria-derived activator of caspase (SMAC) mimetics, which target IAPs, have potential to trigger cancer cell death and sensitize tumor cells to cytotoxic therapy. The aim of this study was to investigate the anti-tumor potential of a novel bivalent SMAC mimetic, APG-1387, in hepatocellular carcinoma (HCC). The mRNA and protein expressions of IAPs, including cellular IAPs (cIAP1 and cIAP2) and X chromosome-linked IAP (XIAP), were increased in HCC tumors compared with normal liver tissue. APG-1387 treatment alone significantly reduced the protein levels of IAPs, but had only a modest effect on the viability and apoptosis of HCC cells in vitro. However, APG-1387 in combination with tumor necrosis factor-alpha (TNF-α) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) significantly reduced cell viability and proliferation, and induced apoptosis in HepG2 cells, as well as in HCCLM3 cells that harbors cancer stem cell-like properties. These synergistic killing effects were caspase-dependent and partially dependent on RIPK1 kinase activity. Furthermore, APG-1387 also promoted the killing effect of Natural Killer cells on HCC cells in vitro and the combination therapy significantly inhibited tumor growth by inducing cell apoptosis in xenograft mice model. In conclusion, our study clarified that APG-1387 could sensitize HCC cells to cytokines or immune cells mediated cell killing and implied that potential of SMAC mimetic based combination immunotherapy for HCC treatment.
Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway
J Exp Clin Cancer Res 2018 Mar 12;37(1):53.PMID:29530056DOI:10.1186/s13046-018-0703-9.
Background: Ovarian cancer is a deadly disease. Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. Overexpression of IAPs proteins has been correlated with tumorigenesis, treatment resistance and poor prognosis. Reinstalling functional cell death machinery by pharmacological inhibition of IAPs proteins may represent an attractive therapeutic strategy for treatment of ovarian cancer. Methods: CCK-8 and colony formation assay was performed to examine cytotoxic activity. Apoptosis was analyzed by fluorescence microscopy, flow cytometry and TUNEL assay. Elisa assay was used to determine TNFα protein. Caspase activity assay was used for caspase activation evaluation. Immunoprecipitation and siRNA interference were carried out for functional analysis. Western blotting analysis were carried out to test protein expression. Ovarian cancer cell xenograft nude mice model was used for in vivo efficacy evaluation. Results: APG-1387 demonstrated potent inhibitory effect on ovarian cancer cell growth and clonogenic cell survival. APG-1387 induced RIP1- and TNFα-dependent apoptotic cell death in ovarian cancer through downregulation of IAPs proteins and induction of caspase-8/FADD/RIP1 complex, which drives caspase-8 activation. NF-κB signaling pathway was activated upon APG-1387 treatment and RIP1 contributed to NF-κB activation. APG-1387 induced cytoprotective autophagy while triggering apoptosis in ovarian cancer cells and inhibition of autophagy enhanced APG-1387-induced apoptotic cell death. APG-1387 exhibited potent antitumor activity against established human ovarian cancer xenografts. Conclusions: Our results demonstrate that APG-1387 targets IAPs proteins to potently elicit apoptotic cell death in vitro and in vivo, and provide mechanistic and applicable rationale for future clinical evaluation of APG-1387 in ovarian cancer.
A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis
Cancer Lett 2016 Oct 10;381(1):14-22.PMID:27424523DOI:10.1016/j.canlet.2016.07.008.
Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC.
A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on HBV-positive hepatocellular carcinoma with high expression of cIAP2 by inducing apoptosis and enhancing innate anti-tumor immunity
Biochem Pharmacol 2018 Aug;154:127-135.PMID:29679556DOI:10.1016/j.bcp.2018.04.020.
Check point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, Second mitochondria-derived activator of caspases (SMAC) mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs). In our study, firstly, we found that HCC patients with copy number alteration of cIAP1, cIAP2, and XIAP had a dismal prognosis. Then, we discovered that APG-1387 alone could induce apoptosis of PLC/PRF/5 which was HBV positive both in-vitro and in-vivo. Furthermore, we found that APG-1387 significantly up-regulated the expression of calreticulin and HLA-DR in PLC/PRF/5 via activating non-classic NF-κB pathway. Also, compared to vehicle group, APG-1387 increased NK cell counts by 5 folds in PLC/PRF/5 xenograft model. In-vitro, APG-1387 positively regulated T cells by reducing Treg differentiation and down-regulating PD1 expression in CD4 T cell. Moreover, APG-1387 had no impact on memory T cells. Consequently, our results suggest that APG1387 could be a good candidate to combine with anti-PD1 antibody treatment to overcome low responds of check point inhibitors in HBV positive HCC.
Correction to: Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway
J Exp Clin Cancer Res 2018 May 24;37(1):108.PMID:29793514DOI:10.1186/s13046-018-0774-7.
In the publication of this article [1], there was an error in Figs. 2, 3 and 6.