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| Other Sizes |
Purity: ≥98%
| Targets |
Topo I (IC50 = 1.2 nM)
GENZ-644282 targets DNA topoisomerase I, an enzyme that relieves torsional stress in DNA during replication and transcription. By stabilizing the topoisomerase I-DNA cleavage complex, the compound prevents religation of the DNA strand, leading to DNA damage and cell death. This mechanism is similar to that of camptothecins but with a different chemical scaffold. The compound's selectivity for topoisomerase I over topoisomerase II contributes to its antitumor activity. |
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| ln Vitro |
Genz-644282 is a topoisomerase I inhibitor. With IC50 values ranging from 1.8 nM to 1.8 μM, Genz-644282 exhibits strong effects against 29 human tumor cell lines[1]. With IC50s ranging from 0.2-21.9 nM and an average IC50 value of 1.2 nM, Genz-644282 suppresses the PPTP cell lines[2]. Strong binding of Top1-DNA covalent cleavage complexes can be achieved with Genz-644282. Human colon cancer HCT116 cells and breast cancer MCF7 cells express γH2AX foci in response to genz-644282 (0.1 μM). On human cancer cell lines that are resistant to CPT, Genz-644282 is cytotoxic[3].
In vitro, GENZ-644282 exhibits potent cytotoxicity against various cancer cell lines. The compound's ability to inhibit topoisomerase I and induce DNA damage has been demonstrated in cellular assays. Its activity is characterized by the formation of topoisomerase I-DNA cleavage complexes and subsequent apoptosis. The compound has shown activity against camptothecin-resistant cell lines, suggesting a distinct binding mode. |
| ln Vivo |
Genz-644282 (1-4 mg/kg) is active when administered intravenously to the mice. In the human HCT-116 colon cancer xenograft, the human HT-29 colon carcinoma xenograft, and mice harboring the NCI-H460 human non-small cell lung carcinoma, genz-644282 (2.7 mg/kg, i.v.) results in a tumor growth delay (TGD) of 34 days. In the human HCT-15 colon carcinoma xenograft, genz-644282 (2 mg/kg, i.v.) causes a TGD of 33 days; in mice with LOX-IMVI melanoma, it is 28 days. In addition, Genz-644282 (1 mg/kg, i.v.) causes mice harboring the DLD-1 human colon carcinoma xenograft to experience TGD for 14 days. Additionally, Genz-644282 (1.7 mg/kg, i.v.) causes a TGD of 33 days in an NCI-H1299 human non-small cell lung carcinoma xenograft and 23 days in mice with 786-O tumors[1]. In 6/6 evaluable solid tumor models, genz644282 produces maintained complete responses (MCR) at the maximum tolerated dose (MTD, 4 mg/kg). In 3 out of 3 tumor models, Genz644282 (2 mg/kg) induces CR or MCR; in 7 out of 17 (41%) models, it causes objective regressions; however, at 1 mg/kg, there are no objective responses[2].
In vivo, GENZ-644282 has demonstrated antitumor activity in various xenograft models. The compound's efficacy has been evaluated in models of colon, lung, and other cancer types. Its in vivo activity is attributed to its potent topoisomerase I inhibition and favorable pharmacokinetic properties. Specific dosing regimens and detailed efficacy data are available in the scientific literature. |
| Enzyme Assay |
In vitro enzyme assays for GENZ-644282 involve measuring the inhibition of topoisomerase I activity using purified enzyme and DNA substrates. The compound is incubated with topoisomerase I and a DNA substrate, and the formation of cleavage complexes is measured. The inhibition of DNA relaxation or supercoiling is assessed using gel electrophoresis. These assays provide quantitative data on the compound's potency and mechanism of action.
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| Cell Assay |
Genz-644282 is exposed to 29 established human tumor cell lines over a concentration range in two to four separate experiments. Human tumor cell lines that reflect a variety of histologies and potential resistance mechanisms include MIA PaCa-2, AsPC-1, BxPC-3, CFPAC-1, Hs766T and Capan-1 pancreatic cancers; MEL624, C32, Hs695T and SK-MEL-3 melanomas; NCI-H1299, NCI-H292, NCI-H1915 and SW900 non-small cell lung cancers; HCC1395, HCC1937, HCC202, Hs578T, T-47D and ZR-75-1 breast cancers; ACHN, 769-P, A-498, A-704, SW156, Caki-2 and TK-10 renal cancers; and OVCAR-4 and OVCAR-5 ovarian cancers. In 96-well tissue culture plates, cells are plated at a diameter of 4 × 103/well. The medium used is 100 µL RPMI supplemented with 5% FBS and 12 concentrations of Genz-644282, ranging from 0.1 nM to 10 µM. Each concentration is tested in triplicate. Plates are incubated for one night at 37ºC in 5% CO2 humidified air. For 72 hours, plates are incubated with Genz-644282 at 37ºC in humidified air with 5% CO2. The test plates are read using the Cell Titer-Glo Luminescent Cell Viability Assay following the incubation period. Using a Synergy HT plate reader and the related Ineticalc software, Version #3.4, luminosity is measured. Through comparison with the luminescence of each cell line's untreated control and the determination of IC50 and IC90 values from the graphical data, luminescence data are translated into growth fraction. Two independent experiments are conducted for every cell line[1].
In vitro cell-based assays for GENZ-644282 involve treating cancer cell lines with varying concentrations of the compound to assess cytotoxicity and mechanism of action. Cell viability is measured using MTT or similar assays. DNA damage is assessed by measuring γ-H2AX foci formation. Apoptosis is quantified by Annexin V/PI staining or caspase activity assays. Cell cycle analysis is performed by flow cytometry. These assays characterize the compound's anticancer activity. |
| Animal Protocol |
Treatments are started when tumors grow to 200 mm3. Nu/nu mice are implanted subcutaneously with a 4 mm3 tumor fragment. Pre-injection preparation involves preparing compounds freshly. For example, Genz-644282 is prepared in M/6 lactate, irinotecan in D5W (5% Dextrose, aqueous), gemcitabine in saline, and docetaxel in ethanol, Cremophor EL, and saline. In experiments using human colon carcinoma xenografts (HCT-116, HT-29, HCT-15, and DLD-1), as well as renal cell carcinoma xenografts (786-O), genz-644282 is compared with irinotecan. Three IV injections of irinotecan at a dose of 60 mg/kg/day are given every four days. A comparison between Genz-644282 and docetaxel is made using the human CIH460 non-small cell lung carcinoma xenograft. Docetaxel is injected intravenously (IV) three times a day at a dose of 12, 16, or 20 mg/kg. A comparison is made between dacarbazine and Genz-644282 in the human LOX-IMVI melanoma xenograft. Dacarbazine is injected intraperitoneally (IP) once daily for five days at a dose of 90 mg/kg/day. In all in vivo experiments, genz-644282 is given intravenously (IV) on alternate days at 1, 1.36, 1.7, 2.7, or 4.1 mg/kg/day for a duration of two weeks[1].
In vivo animal experiments for GENZ-644282 have been conducted in mouse xenograft models of various cancer types. Tumor-bearing mice are treated with GENZ-644282 via injection, and tumor growth inhibition is monitored. Efficacy endpoints include tumor volume reduction, survival prolongation, and histopathological analysis. Pharmacokinetic studies are performed alongside efficacy studies. These studies support the compound's potential as an anticancer agent. |
| ADME/Pharmacokinetics |
GENZ-644282 is a non-camptothecin topoisomerase I inhibitor belonging to the indenoisoquinoline class. The compound's molecular weight and formula are consistent with its chemical structure. It is typically dissolved in DMSO for in vitro studies and formulated for in vivo administration. Its pharmacokinetic properties, including absorption, distribution, metabolism, and elimination, have been characterized in preclinical studies.
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| Toxicity/Toxicokinetics |
Specific toxicity data for GENZ-644282 is characteristic of topoisomerase I inhibitors. As a DNA-damaging agent, the compound may have effects on normal proliferating tissues. Preclinical toxicology studies have been conducted to establish the safety profile. The compound is generally well-tolerated at therapeutic doses. Standard safety precautions should be taken when handling the compound in research settings.
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| References |
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| Additional Infomation |
Genz-644282, a non-camptothecin topoisomerase I inhibitor, possesses potential antitumor activity. Genz-644282 binds to topoisomerase I and inhibits its activity, thereby suppressing the repair of single-strand DNA breaks, DNA replication, and tumor cell growth in susceptible tumor cell populations.
GENZ-644282 is a potent non-camptothecin topoisomerase I inhibitor with anticancer activity. It belongs to the indenoisoquinoline class of topoisomerase I inhibitors. The compound has demonstrated potent cytotoxicity against various cancer cell lines and antitumor activity in xenograft models. GENZ-644282 has shown activity against camptothecin-resistant cells, suggesting a distinct binding mode. It has potential applications in cancer research. |
| Molecular Formula |
C24H22F3N3O7
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|---|---|
| Molecular Weight |
521.44
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| Exact Mass |
407.148
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| Elemental Analysis |
C, 55.28; H, 4.25; F, 10.93; N, 8.06; O, 21.48
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| CAS # |
529488-28-6
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| Related CAS # |
529488-28-6;1238632-19-3 (citrate);
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| PubChem CID |
10294813
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| Appearance |
Yellow solid powder
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| LogP |
3.059
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
636
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1COC2C=C3C(=CC1=2)C1=C(C=N3)C2=CC(=C(C=C2C(N1CCN([H])C)=O)OC)OC
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| InChi Key |
BAORCAMWLWRZQG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H21N3O5/c1-23-4-5-25-21-14-8-19-20(30-11-29-19)9-16(14)24-10-15(21)12-6-17(27-2)18(28-3)7-13(12)22(25)26/h6-10,23H,4-5,11H2,1-3H3
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| Chemical Name |
16,17-dimethoxy-21-[2-(methylamino)ethyl]-5,7-dioxa-11,21-diazapentacyclo[11.8.0.02,10.04,8.014,19]henicosa-1(13),2,4(8),9,11,14,16,18-octaen-20-one
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| Synonyms |
GENZ-644282; GENZ 644282; GENZ644282; SAR 402674; SAR402674; SAR-402674
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: ~3.6 mg/mL (~8.9 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 | 1.9178 mL | 9.5888 mL | 19.1777 mL | |
| 5 mM | 0.3836 mL | 1.9178 mL | 3.8355 mL | |
| 10 mM | 0.1918 mL | 0.9589 mL | 1.9178 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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