PTC-209
目录号 : GC15725
PTC-209 是一种小分子化合物，可选择性抑制 BMI-1，在 HT1080 细胞中的 IC50 为 0.5μM，是一种很有前途的抗癌药物在体外，PTC-209 以 0.1 到 10μM 之间的剂量处理人结直肠癌细胞，以剂量依赖性方式降低 BMI-1 蛋白水平，同时减少细胞生长。
Cas No.:315704-66-6
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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| Cell experiment [1]: | |
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Cell lines |
various cancer cell lines: lung (LNM35, A549), breast (MDA-MB-231 and T47D), and colon (HT-29, HCT-116, and HCT8/S11) |
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Preparation Method |
Cells were seeded at a density of 5000 cells/well into 96-well plates. After 24h, cells were treated for another 24, 48, and 72h with increasing concentrations of PTC-209 (0.01-10 µM) in triplicate. Control cultures were treated with 0.1% DMSO (the drug vehicle). |
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Reaction Conditions |
0.01-10µM PTC-209 for 24, 48, and 72h |
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Applications |
PTC-209 induced a concentration- and time-dependent decrease in the cellular viability of all cell lines tested. Lung cancer cells (LNM35 and A549) showed a higher sensitivity to PTC-209 treatment compared with breast (MDA-MB-231) and colon (HT-29) cancer cells. |
| Animal experiment [2]: | |
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Animal models |
female nude mice, four to six weeks old |
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Preparation Method |
MDA-MB-231 cells were exposed to PTC-209, palbociclib, or combination of the two inhibitors at 5.0µM for 72h. Cells were then trypsinized, washed with PBS, and 2×106 cells were subcutaneously injected into the right left frank of female nude mice in a 100µL mixture (1:1 v/v of PBS/matrigel). The animals were monitored twice weekly and tumor volume was measured using caliper. |
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Dosage form |
MDA-MB-231 cells were exposed to drugs at 5.0µM for 72h |
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Applications |
PTC-209 and palbociclib significantly inhibit the growth of tumor, and combination of both drugs was more efficacious in inhibiting MDA-MB-231 tumor growth in vivo. PTC-209 and palbociclib treatments restricted the invasiveness of MDA-MB-231 cells, while combination group exhibited the most profound restricted invasion of tumor cells compared to other treatment groups and control. |
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References: [1]. Sulaiman S, Arafat K, et al. PTC-209 Anti-Cancer Effects Involved the Inhibition of STAT3 Phosphorylation. Front Pharmacol. 2019;10:1199. Published 2019 Oct 21. [2]. Elango R, Vishnubalaji R, et al. Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo. Sci Rep. 2019;9(1):13696. Published 2019 Sep 23. |
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PTC-209, a low-molecular-weight compound that selectively inhibits BMI-1 with IC50 for 0.5μM in HT1080 cells, is a promising anticancer[1,2]
In vitro, PTC-209 treats human colorectal cancer cells with doses between 0.1 and 10μM reduced BMI-1 protein levels in a dose-dependent manner with a concomitant reduction in cell growth[1]. PTC-209 causes a concentration- and time-dependent decrease in the cellular viability of lung cancer cells (LNM35 and A549), breast cancer cells (MDA-MB-231 and T47D), and colon cancer cells (HT-29, HCT8/S11, and HCT-116)[2]. Treatment with PTC-209 significantly decreased viable cell numbers in human multiple myeloma (MM) cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. In the MM microenvironment, PTC-209 impaired tube formation, impaired osteoclast development and decreased osteoblast formation in a dose-dependent manner (P < 0.01 at 1μM, respectively). Therapeutic targeting of BMI-1 by PTC-209 is a promising novel therapeutic intervention for MM[3]
PTC-209 combined with palbociclib inhibit tumor cell proliferation, sphere and colony formation, migration, and in vivo tumor formation[4]. PTC-209 administration significantly reduced tumor growth in a HNSCC xenograft model by Bmi1 inhibition and impaired cell proliferation in vivo[5]. PTC-209 significantly attenuates the glioblastoma growth in a murine orthotopic xenograft model[6]
References:
[1].Kreso A, van Galen P, et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014;20(1):29-36.
[2].Sulaiman S, Arafat K, et al. PTC-209 Anti-Cancer Effects Involved the Inhibition of STAT3 Phosphorylation. Front Pharmacol. 2019;10:1199. Published 2019 Oct 21.
[3].Bolomsky A, Schlangen K, et al. Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment. J Hematol Oncol. 2016;9:17. Published 2016 Mar 2.
[4]. Elango R, Vishnubalaji R, et al. Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo. Sci Rep. 2019;9(1):13696. Published 2019 Sep 23.
[5].Wang Q, Li Z, et al. Pharmacological inhibition of Bmi1 by PTC-209 impaired tumor growth in head neck squamous cell carcinoma. Cancer Cell Int. 2017;17:107. Published 2017 Nov 21.
[6].Kong Y, Ai C, et al. Targeting of BMI-1 with PTC-209 inhibits glioblastoma development. Cell Cycle. 2018;17(10):1199-1211
PTC-209 是一种小分子化合物，可选择性抑制 BMI-1，在 HT1080 细胞中的 IC50 为 0.5μM，是一种很有前途的抗癌药物[1,2]
在体外，PTC-209 以 0.1 到 10μM 之间的剂量处理人结直肠癌细胞，以剂量依赖性方式降低 BMI-1 蛋白水平，同时减少细胞生长[1]。 PTC-209 导致肺癌细胞（LNM35 和 A549）、乳腺癌细胞（MDA-MB-231 和 T47D）和结肠癌细胞（HT-29、HCT8/ S11 和 HCT-116)[2]。用 PTC-209 处理可显着降低人多发性骨髓瘤 (MM) 细胞系中的活细胞数量，诱导 G1 细胞周期停滞，促进细胞凋亡，并证明与泊马度胺和卡非佐米具有协同活性。在 MM 微环境中，PTC-209 以剂量依赖性方式损害管形成、损害破骨细胞发育和减少成骨细胞形成（P <；1μM 时分别为 0.01）。 PTC-209 对 BMI-1 的治疗靶向是一种很有前途的 MM 新型治疗干预措施[3]
PTC-209 联合 palbociclib 可抑制肿瘤细胞增殖、球体和集落形成、迁移以及体内肿瘤形成[4]。 PTC-209 给药通过 Bmi1 抑制和体内细胞增殖受损显着降低了 HNSCC 异种移植模型中的肿瘤生长[5]。 PTC-209 显着减弱小鼠原位异种移植模型中的胶质母细胞瘤生长[6]
| Cas No. | 315704-66-6 | SDF | |
| 化学名 | N-(2,6-dibromo-4-methoxyphenyl)-4-(2-methylimidazo[1,2-a]pyrimidin-3-yl)-1,3-thiazol-2-amine | ||
| Canonical SMILES | CC1=C(N2C=CC=NC2=N1)C3=CSC(=N3)NC4=C(C=C(C=C4Br)OC)Br | ||
| 分子式 | C17H13Br2N5OS | 分子量 | 495.19 |
| 溶解度 | ≥ 24.75mg/mL 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 | 2.0194 mL | 10.0971 mL | 20.1943 mL |
| 5 mM | 0.4039 mL | 2.0194 mL | 4.0389 mL |
| 10 mM | 0.2019 mL | 1.0097 mL | 2.0194 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。
PTC-209 Anti-Cancer Effects Involved the Inhibition of STAT3 Phosphorylation
Introduction: Lung, breast, and colorectal cancers are the leading causes of cancer-related deaths despite many therapeutic options, including targeted therapy and immunotherapies. Methods: Here, we investigated the impact of PTC-209, a small-molecule Bmi-1 inhibitor, on human cancer cell viability alone and in combination with anticancer drugs, namely, cisplatin, oxaliplatin, 5-fluorouracil, camptothecin, and Frondoside-A and its impact on cellular migration and colony growth in vitro and on tumor growth in ovo. Results: We demonstrate that PTC-209 causes a concentration- and time-dependent decrease in the cellular viability of lung cancer cells (LNM35 and A549), breast cancer cells (MDA-MB-231 and T47D), and colon cancer cells (HT-29, HCT8/S11, and HCT-116). Similarly, treatment with PTC-209 significantly decreased the growth of LNM35, A549, MDA-MB-231, and HT-29 clones and colonies in vitro and LNM35 and A549 tumor growth in the in ovo tumor xenograft model. PTC-209 at the non-toxic concentrations significantly reduced the migration of lung (LNM35 and A549) and breast (MDA-MB-231) cancer cells. Moreover, we show that PTC-209, at a concentration of 1 μM, enhances the anti-cancer effects of Frondoside-A in lung, breast, and colon cancer cells, as well as the effect camptothecin in breast cancer cells and the effect of cisplatin in lung cancer cells in vitro. However, PTC-209 failed to enhance the anti-cancer effects of oxaliplatin and 5-fluorouracil in colon cancer cells. Treatment of lung, breast, and colon cancer cells with PTC-209 (1 and 2.5 μM) for 48 h showed no caspase-3 activation, but a decrease in the cell number below the seeding level suggests that PTC-209 reduces cellular viability probably through inhibition of cell proliferation and induction of cell death via a caspase-3-independent mechanism. Molecular mechanism analysis revealed that PTC-209 significantly inhibited the STAT3 phosphorylation by decreasing the expression level of gp130 as early as 30 min post-treatment. Conclusion: Our findings identify PTC-209 as a promising anticancer agent for the treatment of solid tumors either alone and/or in combination with the standard cytotoxic drugs cisplatin and camptothecin and the natural product Frondoside-A.
Targeting of BMI-1 with PTC-209 inhibits glioblastoma development
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor and refractory to existing therapies. The oncogene BMI-1, a member of Polycomb Repressive Complex 1 (PRC1) plays essential roles in various human cancers and becomes an attractive therapeutic target. Here we showed that BMI-1 is highly expressed in GBM and especially enriched in glioblastoma stem cells (GSCs). Then we comprehensively investigated the anti-GBM effects of PTC-209, a novel specific inhibitor of BMI-1. We found that PTC-209 efficiently downregulates BMI-1 expression and the histone H2AK119ub1 levels at microM concentrations. In vitro, PTC-209 effectively inhibits glioblastoma cell proliferation and migration, and GSC self-renewal. Transcriptomic analyses of TCGA datasets of glioblastoma and PTC-209-treated GBM cells demonstrate that PTC-209 reverses the altered transcriptional program associated with BMI-1 overexpression. And Chromatin Immunoprecipitation assay confirms that the derepressed tumor suppressor genes belong to BMI-1 targets and the enrichment levels of H2AK119ub1 at their promoters is decreased upon PTC-209 treatment. Strikingly, the glioblastoma growth is significantly attenuated by PTC-209 in a murine orthotopic xenograft model. Therefore our study provides proof-of-concept for inhibitors targeting BMI-1 in potential applications as an anti-GBM therapy.
Bmi1 inhibitor PTC-209 promotes Chemically-induced Direct Cardiac Reprogramming of cardiac fibroblasts into cardiomyocytes
The development of therapeutic approaches based on direct cardiac reprogramming of fibroblasts into induced-cardiomyocytes (iCM) has emerged as an attractive strategy to repair the injured myocardium. The identification of the mechanisms driving lineage conversion represents a crucial step toward the development of new and more efficient regenerative strategies. To this aim, here we show that pre-treatment with the Bmi1 inhibitor PTC-209 is sufficient to increase the efficiency of Chemical-induced Direct Cardiac Reprogramming both in mouse embryonic fibroblasts and adult cardiac fibroblasts. PTC-209 induces an overall increase of spontaneously beating iCM at end-stage of reprogramming, expressing high levels of late cardiac markers Troponin T and myosin muscle light chain-2v. The inhibition of Bmi1 expression occurring upon PTC-209 pre-treatment was maintained throughout the reprogramming protocol, contributing to a significant gene expression de-regulation. RNA profiling revealed that, upon Bmi1 inhibition a significant down-regulation of genes associated with immune and inflammatory signalling pathways occurred, with repression of different genes involved in interleukin, cytokine and chemokine pathways. Accordingly, we observed the down-regulation of both JAK/STAT3 and MAPK/ERK1-2 pathway activation, highlighting the crucial role of these pathways as a barrier for cardiac reprogramming. These findings have significant implications for the development of new cardiac regenerative therapies.
Glucose and Cell Context-Dependent Impact of BMI-1 Inhibitor PTC-209 on AKT Pathway in Endometrial Cancer Cells
Purpose: In our study, the glucose and cell context-dependent impact of the BMI-1 inhibitor PTC-209 on the AKT pathway in endometrial cancer cells was determined.
Methods: The expression of BMI-1 was inhibited by PTC-209 in endometrial cancer cells HEC-1A and Ishikawa stimulated with insulin and grown in different glucose concentrations. The migration, invasion, viability, and proliferative potential after PTC-209 treatment was assessed using wound-healing, Transwell assay, Matrigel-coated inserts, and MTT tests. Chromatin immunoprecipitation was used to determine the localization of BMI-1 protein at promoter sites of the genes tested.
Results: BMI-1 inhibition caused an increase in PHLPP1/2 expression and a decrease in phospho-AKT level in both cell lines. The glucose concentration and insulin stimulation differentially impact the AKT pathway through BMI-1 in cells differing in PTEN statuses. The expression of BMI-1 is dependent on the glucose concentration and insulin stimulation mostly in PTEN positive HEC-1A cells. In high glucose concentrations, BMI-1 affects AKT activity through PHLPPs and in hypoglycemia mostly through PTEN. BMI-1 inhibition impacts on genes involved in SNAIL, SLUG, and CDH1 and reduces endometrial cancer cells' migratory and invasive potential.
Conclusions: Our results indicate that the relationship between BMI-1 and phosphatases involved in AKT regulation depends on the glucose concentration and insulin stimulation.
The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells
BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 ?M). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC.