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PTC596 is a novel, orally bioavailable and selective B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) inhibitor. PTC596 targets BMI1 expressed by both tumor cells and cancer stem cells (CSCs), and induces hyper-phosphorylation of BMI1, leading to its degradation. PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells.
| ln Vitro |
Unesbulin (PTC596; 20-200 nM; for 48 hours) causes apoptosis in AML cells in a p53-independent way. Overexpression of BMI-1 renders AML cells insensitive to PTC596-induced apoptosis [1]. Unesbulin (200 nM; for 10 hours) promotes accumulation of cells in G2/M phase [1]. Unesbulin (0.012-1 μM; for 20 hours) dramatically lowers BMI-1 protein levels [1]. Unesbulin inhibits APC/CCDC20 activity, resulting to persistent activation of CDK1 and CDK2, ultimately causing hyperphosphorylation of BMI1 [2].
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| ln Vivo |
Mice survival can be markedly prolonged by unesbulin (PTC596; 5 mg/kg; oral gavage; once every 3 days for 13 days) [1]. Compared to control SCID mice with K562 cells, unesbulin (20 mg/kg; oral gavage; once weekly for 15 days) produced noticeably smaller tumor volumes [1]. The oral gavage of unesbulin (10 or 12.5 mg/kg) twice weekly until death was found to significantly extend the survival of NOD-SCID mice bearing HL-60 cells compared to the vehicle-treated group [1].
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| Cell Assay |
Apoptosis analysis[1]
Cell Types: AML cell lines (MOLM-13, OCI-AML3, MOLM-14, MV4-11, U-937, HL-60) Tested Concentrations: 20, 50, 100, 200 nM Incubation Duration: For 48 hrs (hours) Experimental Results: Induced apoptosis in a dose- and time-dependent manner, with average IC50 and ED50 values of 30.7 nM and 60.3 nM, respectively, across the six cell lines. Cell cycle analysis [1] Cell Types: MOLM-13 and U-937 Cell Tested Concentrations: 200 nM Incubation Duration: 10 hrs (hours) Experimental Results: Result in accumulation of cells in G2/M phase, while the percentage of cells in G1 phase decreases. Western Blot Analysis[1] Cell Types: MOLM-13 Cell Tested Concentrations: 0.012, 0.037, 0.11, 0.33, 1 μM Incubation Duration: 20 hrs (hours) Experimental Results: Significant protein levels of BMI-1 and its downstream target ubiquitinated histone H2A reduce. Cyclin B1 and securin levels are increased. |
| Animal Protocol |
Animal/Disease Models: NOD-SCID/IL2Rγ-KO (NSG) mice with MOLM-13 cells [1]
Doses: 5 mg/kg Route of Administration: po (oral gavage); once every 3 days for 13 days Experimental Results: vs. Mice survived Dramatically longer than vehicle-treated mice in a dose-dependent manner. |
| References | |
| Additional Infomation |
Unesbulin is an orally active inhibitor of the polycomb ring finger oncogene BMI1 (B-cell-specific Moloney murine leukemia virus integration site 1), with potential antineoplastic activity. Upon oral administration, unesbulin targets BMI1 expressed by both tumor cells and cancer stem cells (CSCs), and induces hyper-phosphorylation of BMI1 leading to its degradation. This inhibits BMI1-mediated signal transduction pathways and results in a reduction of proliferation of BMI1-expressing tumor cells. BMI1, a key protein in the polycomb repressive complex 1 (PRC1), is overexpressed in certain tumor cell types, and plays a key role in CSC survival, proliferation and resistance to chemotherapeutics; its expression is associated with increased tumor aggressiveness and a poor prognosis.
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| Molecular Formula |
C₁₉H₁₃F₅N₆
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| Molecular Weight |
420.3387
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| Exact Mass |
420.112
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| CAS # |
1610964-64-1
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| Related CAS # |
1610964-64-1;Unesbulin HCl;
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| PubChem CID |
74223469
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
583.9±60.0 °C at 760 mmHg
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| Flash Point |
307.0±32.9 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.645
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| LogP |
3.68
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
30
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| Complexity |
586
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
TWLWOOPCEXYVBE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H13F5N6/c1-9-26-13-7-4-11(20)8-14(13)30(9)18-28-16(25)15(21)17(29-18)27-12-5-2-10(3-6-12)19(22,23)24/h2-8H,1H3,(H3,25,27,28,29)
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| Chemical Name |
5-Fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N4-(4-(trifluoromethyl)phenyl)pyrimidine-4,6-diamine
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| Synonyms |
PTC596 PTC-596 PTC 596
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~16.67 mg/mL (~39.66 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.97 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (3.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3790 mL | 11.8951 mL | 23.7903 mL | |
| 5 mM | 0.4758 mL | 2.3790 mL | 4.7581 mL | |
| 10 mM | 0.2379 mL | 1.1895 mL | 2.3790 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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