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| Targets |
Berubicin targets DNA and topoisomerase II (Top II). As an anthracycline, it inhibits the topoisomerase II enzyme, which is essential for DNA replication and transcription. Berubicin also intercalates between base pairs of the DNA/RNA strand, disrupting DNA and RNA synthesis. This dual mechanism of action leads to DNA damage, cell cycle arrest, and apoptosis in cancer cells. Berubicin's ability to cross the blood-brain barrier is a key feature that makes it a promising candidate for treating brain tumors.
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| ln Vitro |
K562 cell activity is inhibited by WP 769 hydrochloride, with an IC50 value of 0.18 mg/mL[1]. A 24-hour exposure to WP 769 Hydrochloride (0-100 µM) inhibits the absorption of the thymic circuit guideline by KBM-5 cells [2]. In KBM-5 cells, WP 769 hydrochloride (1 µM; 15 min) activates NF-κB via the p50 and p65 NF-κB subunits [2]. In a dose-dependent manner, WP 769 Hydrochloride (0-100 µM; 72 h) inhibits the Jurkat and RIP buffer cell viability experiment [2].
In vitro, Berubicin has been shown to inhibit topoisomerase II activity and induce DNA damage in cancer cell lines. Its activity is typically measured using cell-based assays that assess cell viability, DNA synthesis, and apoptosis. The compound's ability to cross the blood-brain barrier has been demonstrated in preclinical studies. In vitro studies have confirmed Berubicin's potent anti-cancer activity against various cancer cell lines, including glioblastoma cells. |
| ln Vivo |
In vivo, Berubicin has been evaluated in clinical trials for the treatment of recurrent or progressive glioblastoma multiforme (GBM). A Phase 2 clinical trial has been completed, with results expected in the first half of 2025. The compound has been administered to humans in 4 clinical trials to date. Berubicin has shown promise in treating GBM, a highly aggressive brain tumor with limited treatment options. The compound's ability to cross the blood-brain barrier is a significant advantage for treating brain tumors.
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| Enzyme Assay |
In vitro enzyme assays for Berubicin measure its inhibition of topoisomerase II activity. Topoisomerase II enzyme is incubated with DNA and ATP in the presence of varying concentrations of Berubicin. The relaxation or cleavage of DNA is measured, and the IC50 is determined from the dose-response curve. DNA intercalation can be assessed using DNA binding assays, such as fluorescence quenching or ethidium bromide displacement assays. These assays confirm Berubicin's mechanism of action as a topoisomerase II inhibitor and DNA intercalator.
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| Cell Assay |
Cell viability assay [3]
Cell Types: SH-SY5Y cells. Tested Concentrations: 0.1, 1 and 10 µM. Incubation Duration: 0, 1, 2, 3, 4 and 5 days. Experimental Results: Cell viability was inhibited in a dose-dependent manner. Apoptosis analysis [3] Cell Types: SH-SY5Y cells. Tested Concentrations: 50, 500 and 2000 nM. Incubation Duration: 48 hrs (hours). Experimental Results: Promote cell apoptosis. Western Blot Analysis[3] Cell Types: SH-SY5Y cells. Tested Concentrations: 0, 0.1, 1.0 or 10 µM. Incubation Duration: 0, 0.5, 1, 2, 4, 6, 8, 12 or 24 hrs (hours). Experimental Results: Casp 3 and Casp 9 are activated. p53 and NF-κB expression increased. IκBα expression is diminished. In vitro cell-based assays for Berubicin are used to study its effects on cancer cell lines. Cells are treated with Berubicin at various concentrations, and cell viability is assessed using assays such as MTT or CellTiter-Glo. DNA synthesis is measured by incorporation of labeled nucleotides. Apoptosis is measured using Annexin V staining or caspase-3/7 activation assays. Cell cycle analysis is performed by flow cytometry. These assays confirm the compound's anti-cancer activity and its effects on DNA synthesis and cell cycle progression. |
| Animal Protocol |
In vivo animal experiments for Berubicin have been conducted in preclinical models of cancer, including glioblastoma xenografts. In a typical study, mice bearing tumor xenografts are treated with Berubicin, and tumor growth is monitored. The compound's ability to inhibit tumor growth and improve survival is assessed. Pharmacokinetic studies have also been conducted to evaluate the compound's distribution, including its ability to cross the blood-brain barrier. These studies support the clinical development of Berubicin for brain tumors.
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| ADME/Pharmacokinetics |
Berubicin has a molecular formula of C34H36ClNO11. It is a solid compound. It is soluble in DMSO and other organic solvents. For storage, it is recommended to keep the powder at -20°C. Pharmacokinetic properties have been characterized in preclinical and clinical studies. Berubicin is the first anthracycline to appear to cross the blood-brain barrier. Detailed pharmacokinetic parameters, such as half-life and bioavailability, are available from clinical trial data.
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| Toxicity/Toxicokinetics |
Detailed toxicity data for Berubicin is available from its clinical development. As an anthracycline, it is expected to have side effects similar to other drugs in this class, including myelosuppression, cardiotoxicity, and gastrointestinal disturbances. In clinical trials, adverse events occurring in more than 10% of patients have been reported. The safety profile of Berubicin is being evaluated in ongoing clinical studies. As with all research chemicals and pharmaceuticals, it should be handled with caution.
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| References |
[1]. WP744, a novel anthracycline with enhanced proapoptotic and antileukemic activity. Anticancer Res. 2001 Nov-Dec;21(6A):3777-84.
[2]. Evidence that activation of nuclear factor-kappaB is essential for the cytotoxic effects of doxorubicin and its analogues. Biochem Pharmacol. 2004 Jan 15;67(2):353-64. [3]. Nuclear factor-kappa B and apoptosis inducing factor activation by doxorubicin analog WP744 in SH-SY5Y neuroblastoma cells. J Surg Res. 2004 Dec;122(2):231-9. |
| Additional Infomation |
RTA 744 is a novel anthracycline derivative capable of crossing the blood-brain barrier, showing significant potential in the treatment of primary and metastatic brain cancer. Anthracyclines are among the most widely used and effective anticancer drugs; however, they have not yet been used to treat brain cancer because current therapies cannot cross the blood-brain barrier. Belubiscin hydrochloride is the hydrochloride salt of the anthracycline derivative belubiscin and possesses potential antitumor activity. Belubiscin can intercalate into DNA and interfere with the activity of topoisomerase II, thereby inhibiting DNA replication and repair, as well as RNA and protein synthesis. Unlike other anthracycline derivatives, this drug can cross the blood-brain barrier (BBB). Drug Indications: Under investigation for the treatment of brain cancer. Mechanism of Action: RTA 744 is an investigational drug for the treatment of adult brain tumors. RTA 744 crosses the blood-brain barrier, blocking an enzyme required for cancer cell growth. RTA 744 is a topoisomerase inhibitor, also known as the topoisomerase II inhibitor RTA 744.
Berubicin HCl is a novel anthracycline antibiotic and topoisomerase II inhibitor. It is a DNA inhibitor that intercalates between base pairs of the DNA/RNA strand, disrupting DNA and RNA synthesis. Berubicin is the first anthracycline to appear to cross the blood-brain barrier. It has been evaluated in clinical trials for the treatment of glioblastoma multiforme (GBM) and has orphan drug and fast track designations in the US. A Phase 2 clinical trial has been completed, with results expected in the first half of 2025. Berubicin is not approved for clinical use. |
| Molecular Formula |
C23H31CLN2O4
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|---|---|
| Molecular Weight |
434.956245660782
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| Exact Mass |
669.198
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| Elemental Analysis |
C, 60.94; H, 5.41; Cl, 5.29; N, 2.09; O, 26.26
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| CAS # |
293736-67-1
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| Related CAS # |
677017-23-1;293736-67-1 (HCl);
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| PubChem CID |
9874591
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| Appearance |
Brown to red solid powder
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| LogP |
3.728
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
47
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| Complexity |
1130
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| Defined Atom Stereocenter Count |
6
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| SMILES |
C1C2=C(CCN3C2CC2=C(C=CC=C2)C3)C=CC=1.O=C(CN(CCO)CCO)O.[H]Cl
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| InChi Key |
GPMIHHFZKBVWAZ-LMMKTYIZSA-N
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| InChi Code |
InChI=1S/C34H35NO11.ClH/c1-16-33(44-15-17-7-4-3-5-8-17)20(35)11-24(45-16)46-22-13-34(42,23(37)14-36)12-19-26(22)32(41)28-27(30(19)39)29(38)18-9-6-10-21(43-2)25(18)31(28)40;/h3-10,16,20,22,24,33,36,39,41-42H,11-15,35H2,1-2H3;1H/t16-,20-,22-,24-,33+,34-;/m0./s1
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| Chemical Name |
(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-6-methyl-5-phenylmethoxyoxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride
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| Synonyms |
WP-769 hydrochloride; Berubicin hydrochloride; Berubicin HCl; 293736-67-1; RTA 744 hydrochloride; WP744; Berubicin HCl; RTA-744; RTA774; WP 769; RTA 744; WP769
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2991 mL | 11.4953 mL | 22.9906 mL | |
| 5 mM | 0.4598 mL | 2.2991 mL | 4.5981 mL | |
| 10 mM | 0.2299 mL | 1.1495 mL | 2.2991 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04915404 | TERMINATED | Drug: Berubicin Hydrochloride | Recurrent Glioblastoma Multiforme | WPD Pharmaceuticals Sp. z o.o. | 2022-12-07 | Phase 1 Phase 2 |
| NCT04762069 | ACTIVE, NOT RECRUITING | Drug: Berubicin Drug: Lomustine |
Glioblastoma Multiforme, Adult | CNS Pharmaceuticals, Inc | 2021-05-18 | Phase 2 |
| NCT05082493 | WITHDRAWN | Drug: Berubicin Hydrochloride | High Grade Glioma | WPD Pharmaceuticals Sp. z o.o | 2023-12 | Phase 1 |
| NCT00538343 | TERMINATED | Drug: berubicin hydrochloride (RTA 744) | Brain Metastases | Reata, a wholly owned subsidiary of Biogen | 2007-10-31 | Phase 2 |
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