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PTC-209

Catalog No.GC15725

PTC-209 Chemical Structure

PTC-209, a low-molecular-weight compound that selectively inhibits BMI-1 with IC50 for 0.5µM in HT1080 cells, is a promising anticancer.

Size Price Stock Qty
10mM (in 1mL DMSO)
$190.00
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2mg
$65.00
In stock
5mg
$73.00
In stock
10mg
$117.00
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50mg
$324.00
In stock

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Sample solution is provided at 25 µL, 10mM.

Quality Control

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Protocol

Cell experiment [1]:

Cell lines

various cancer cell lines: lung (LNM35, A549), breast (MDA-MB-231 and T47D), and colon (HT-29, HCT-116, and HCT8/S11)

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).

Reaction Conditions

0.01-10µM PTC-209 for 24, 48, and 72h

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]:

Animal models

female nude mice, four to six weeks old

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.

Dosage form

MDA-MB-231 cells were exposed to drugs at 5.0µM for 72h

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.

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.

Background

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

Chemical Properties

Cas No. 315704-66-6 SDF
Synonyms N/A
Chemical Name 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
Formula C17H13Br2N5OS M.Wt 495.19
Solubility ≥ 24.75mg/mL in DMSO Storage Store at -20° C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

PTC-209 Anti-Cancer Effects Involved the Inhibition of STAT3 Phosphorylation

Front Pharmacol2019 Oct 21;10:1199.PMID: 31695609DOI: 10.3389/fphar.2019.01199

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.

Bmi1 inhibitor PTC-209 promotes Chemically-induced Direct Cardiac Reprogramming of cardiac fibroblasts into cardiomyocytes

Sci Rep2020 Apr 28;10(1):7129.PMID: 32346096DOI: 10.1038/s41598-020-63992-8

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.

Targeting of BMI-1 with PTC-209 inhibits glioblastoma development

Cell Cycle2018;17(10):1199-1211.PMID: 29886801DOI: 10.1080/15384101.2018.1469872

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.

Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment

J Hematol Oncol2016 Mar 2;9:17.PMID: 26935956DOI: 10.1186/s13045-016-0247-4

Background: The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed in multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel small molecule inhibitor of BMI-1, for its activity in MM.
Methods: BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically available gene expression profiling (GEP) data. The anti-MM activity of PTC-209 was investigated by viability testing, cell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose) polymerase (PARP), JC-1 as well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by quantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast, osteoblast and tube formation was analysed.
Results: We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note, BMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in relapsed/refractory patients treated with bortezomib or dexamethasone. Treatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM activity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1) and v-myc avian myelocytomatosis viral oncogene homolog (MYC) expression as well as upregulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). We also observed upregulation of NOXA (up to 3.6 ± 1.2-fold induction, P = 0.009) and subsequent downregulation of myeloid cell leukemia 1 (MCL-1) protein levels, which likely mediates the apoptotic effects of PTC-209. Importantly, the anti-MM activity was upheld in the presence of stromal support or myeloma growth factors insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6). 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 1 μM, respectively). The latter might be attributed to an induction of DKK1 and was reversed by concurrent anti-DKK1 antibody treatment.
Conclusions: We confirmed overexpression of BMI-1 in MM highlighting its role as an attractive drug target and reveal therapeutic targeting of BMI-1 by PTC-209 as a promising novel therapeutic intervention for MM.

Pharmacological inhibition of Bmi1 by PTC-209 impaired tumor growth in head neck squamous cell carcinoma

Cancer Cell Int2017 Nov 21;17:107.PMID: 29200967DOI: 10.1186/s12935-017-0481-z

Background: Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog) contributes to human tumorigenesis via epigenetic transcriptional silencing and represents a novel therapeutic target with great potentials. Here we sought to determine the therapeutic efficiency of PTC-209, a potent and selective Bmi1 inhibitor, in head neck squamous cell carcinoma (HNSCC) cells and a HNSCC xenograft model.
Methods: The mutation pattern, mRNA level of Bmi1 in HNSCC and its associations with clinicopathological parameters were determined through comprehensive data mining and interrogation using publicly available databases GENT, cBioPortal, Oncomine and TCGA. The PTC-209, a selective and potent Bmi1 inhibitor, was exploited and its effect on Bmi1 expression was measured in two HNSCC cell lines Cal27 and FaDu. The phenotypical changes of HNSCC cells were observed upon PTC-209 treatment in vitro. Moreover, the therapeutic effects of PTC-209 for HNSCC were determined in a xenograft animal model.
Results: Through comprehensive data mining and interrogation, we found that Bmi1 mRNA was frequently overexpressed in a subset of HNSCC samples. Our data revealed that PTC-209 robustly reduced the expression of Bmi1 in Cal27 and FaDu cells presumably by post-transcriptional repression and ubiquitin-proteasomal degradation. PTC-209 treatment resulted in impaired cell proliferation, G1-phase cell cycle arrest, compromised migration and invasiveness, and increased cell apoptosis and chemosensitivity to 5-FU and cisplatin in vitro. Moreover, PTC-209 exposure reduced colony formation, tumorsphere formation and the percentage of ALDH1+ subpopulation in both Cal27 and FaDu cells. Importantly, in vivo PTC-209 administration significantly reduced tumor growth in a HNSCC xenograft model probably by Bmi1 inhibition and impaired cell proliferation.
Conclusions: Our findings indicate that pharmacological inhibition of Bmi1 is a novel therapeutic strategy for HNSCC patients, especially with those with aberrant Bmi1 overexpression.

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