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| Targets |
topoisomerase II alpha topoisomerase II beta
ARN-21934 targets human topoisomerase II alpha (topoIIα) with high selectivity over topoIIβ. Topoisomerase IIα is a nuclear enzyme that is essential for DNA replication and chromosome segregation during cell division. The compound functions as a catalytic inhibitor, meaning it inhibits the enzyme’s catalytic activity without stabilizing the cleavable complex and causing DNA damage. This is in contrast to topoII poisons like etoposide, which stabilize the cleavable complex and induce DNA double-strand breaks. ARN-21934 inhibits DNA relaxation, a key activity of topoIIα, with an IC50 of 2 μM. The compound’s selectivity for topoIIα over topoIIβ suggests that it may have a more favorable safety profile, as topoIIβ inhibition has been linked to secondary malignancies. |
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| ln Vitro |
For topoIIα and topoIIβ, ARN-21934 exhibits a distinct penchant. With an IC50 value of 2 μM for topoIIα-inhibited DNA relaxation and 120 μM for topoIIβ-inhibited DNA relaxation, ARN-21934 is more effective against the α isoform [1]. Human cancer cell lines are displayed in a small panel on ARN-21934. Its IC50 values against melanoma (A375 and G-361), breast (MCF7), endometrial (HeLa), lung (A549), androgen-independent prostate (DU145) cancer cells are 12.6 μM, 8.1 μM, 15.8 μM, 38.2 μM, 17.1 μM, and 11.5 μM, respectively[1].
ARN-21934 has demonstrated potent in vitro activity against topoIIα. The compound inhibits DNA relaxation with an IC50 of 2 μM, which is significantly more potent than etoposide (IC50 = 120 μM). The compound’s activity has been evaluated in 2D cell cultures and 3D in vitro systems. ARN-21934 exhibits excellent metabolic stability and solubility, making it a promising lead compound for drug development. The compound’s anti-proliferative activity against cancer cell lines has been demonstrated, although specific IC50 values have not been detailed in the available literature. |
| ln Vivo |
After fifteen minutes, the intraperitoneal injection of ARN-21934 (10 mg/kg; single dosage) reaches a maximum plasma concentration of 0.68 μg/mL. The half-life in circulation is 149 minutes, and 360 minutes after injection, it is still present in plasma. Additionally, the molecule shows excellent clearance values (0.116 L/(min kg)). Furthermore, ARN-21934 can enter the brain and remains there 360 minutes after injection, reaching its maximal compound concentration in 60 minutes.[1]
ARN-21934 has been evaluated in chick chorioallantoic membrane (CAM) cancer models. The compound demonstrated a tumor growth-arrest effect in these models. The compound’s ability to penetrate the blood-brain barrier (BBB) suggests that it could be effective against brain tumors and other central nervous system malignancies. Further studies would be needed to evaluate the efficacy of ARN-21934 in orthotopic brain tumor models and to characterize its pharmacokinetic and safety profile. |
| Enzyme Assay |
The topoisomerase II inhibitory activity of ARN-21934 can be assessed using in vitro DNA relaxation assays. In a typical assay, purified recombinant human topoIIα is incubated with supercoiled plasmid DNA, ATP, and varying concentrations of ARN-21934. The relaxation of supercoiled DNA to relaxed forms is analyzed by agarose gel electrophoresis. The half-maximal inhibitory concentration (IC50) is calculated from dose-response curves based on the extent of DNA relaxation. The IC50 for ARN-21934 is 2 μM, compared to 120 μM for etoposide. The selectivity for topoIIα over topoIIβ can be assessed by performing similar assays with recombinant topoIIβ.
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| Cell Assay |
The cellular activity of ARN-21934 is assessed using cancer cell lines, including HPV-negative head and neck squamous cell carcinoma (HNSCC) cells. Cells are seeded in 96-well plates and treated with escalating concentrations of ARN-21934 for 48 to 72 hours. Cell viability is measured using MTT or CellTiter-Glo assays, and the half-maximal inhibitory concentration (GI50) values are calculated from dose-response curves. The effects of ARN-21934 on DNA damage and apoptosis are assessed by measuring γH2AX (a marker of DNA double-strand breaks) and caspase-3/7 activity. The compound’s activity has been evaluated in 2D cell cultures and 3D in vitro systems.
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| Animal Protocol |
ARN-21934 has been evaluated in chick chorioallantoic membrane (CAM) cancer models. In these models, tumor cells are implanted onto the CAM of fertilized chicken eggs, and the effects of ARN-21934 on tumor growth are assessed. The compound demonstrated a tumor growth-arrest effect. Future studies may involve the use of orthotopic xenograft models in mice to assess the efficacy of ARN-21934 against brain tumors or other malignancies.
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| ADME/Pharmacokinetics |
ARN-21934 has excellent metabolic stability and solubility, suggesting that it has favorable pharmacokinetic properties. The compound is blood-brain barrier (BBB) penetrant, making it suitable for the treatment of brain tumors. Further studies would be needed to characterize the absorption, distribution, metabolism, and excretion (ADME) properties of ARN-21934 in detail, including oral bioavailability, plasma protein binding, clearance, half-life, and tissue distribution.
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| Toxicity/Toxicokinetics |
No detailed toxicity data for ARN-21934 has been published in the available literature. The compound’s mechanism of action as a catalytic inhibitor of topoIIα, rather than a topoII poison, suggests that it may have a more favorable safety profile compared to classical topoII poisons like etoposide, which are associated with secondary malignancies and cardiotoxicity. However, comprehensive toxicology studies would be required to evaluate the safety profile of ARN-21934 for potential clinical development.
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| References | |
| Additional Infomation |
ARN-21934 is a novel, potent, and highly selective inhibitor of human topoisomerase II alpha (topoIIα), belonging to the 6-amino-tetrahydroquinazoline chemical class. The compound functions as a catalytic inhibitor rather than a topoII poison, with an IC50 of 2 μM for inhibition of DNA relaxation, compared to 120 μM for etoposide. ARN-21934 is highly selective for topoIIα over topoIIβ and is blood-brain barrier (BBB) penetrant. The compound has demonstrated a tumor growth-arrest effect in chick chorioallantoic membrane (CAM) cancer models. ARN-21934 has excellent metabolic stability and solubility, making it a highly promising lead for the development of novel and potentially safer topoII-targeted anticancer drugs.
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| Molecular Formula |
C21H24N6
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|---|---|
| Molecular Weight |
360.4555
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| Exact Mass |
360.206
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| CAS # |
2230854-93-8
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| PubChem CID |
135150944
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| Appearance |
Light yellow to green yellow solid powder
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| LogP |
2.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
458
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N([H])([H])C1([H])C([H])([H])C2C(=NC(C3C([H])=C([H])N=C([H])C=3[H])=NC=2C([H])([H])C1([H])[H])N([H])C1C([H])=C([H])C(=C([H])C=1[H])N(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
CKXSRLUXTFDZCF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H24N6/c1-27(2)17-6-4-16(5-7-17)24-21-18-13-15(22)3-8-19(18)25-20(26-21)14-9-11-23-12-10-14/h4-7,9-12,15H,3,8,13,22H2,1-2H3,(H,24,25,26)
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| Chemical Name |
4-N-[4-(dimethylamino)phenyl]-2-pyridin-4-yl-5,6,7,8-tetrahydroquinazoline-4,6-diamine
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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 : 8.33 mg/mL (23.11 mM)
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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 | 2.7742 mL | 13.8712 mL | 27.7423 mL | |
| 5 mM | 0.5548 mL | 2.7742 mL | 5.5485 mL | |
| 10 mM | 0.2774 mL | 1.3871 mL | 2.7742 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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