Synonym
GENZ644282; GENZ-644282; GENZ 644282; SAR402674; SAR 402674; SAR-402674.
IUPAC/Chemical Name
2,3-dimethoxy-12-(2-(methylamino)ethyl)-[1,3]dioxolo[4',5':4,5]benzo[1,2-h]benzo[c][1,6]naphthyridin-13(12H)-one
InChi Key
BAORCAMWLWRZQG-UHFFFAOYSA-N
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
SMILES Code
O=C1N(CCNC)C2=C(C=NC3=CC(OCO4)=C4C=C32)C5=CC(OC)=C(OC)C=C15
Appearance
Yellow solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
Genz-644282 is a non-camptothecin topoisomerase I inhibitor, used for cancer research.
In vitro activity:
The induction and stability of Top1cc produced by Genz-644282 were evaluated in human colon cancer carcinoma HCT116 cells using the Immunocomplex of Enzyme (ICE) and alkaline elution assays. Figure 3A shows that Genz-644282 is more potent at trapping Top1-DNA covalent cleavage complexes than either CPT or TPT at the same concentration. Additionally, even metabolites of Genz-644282, Genz-649974, Genz-649975, and Genz-649978, are active and effective at trapping Top1 with Genz-649978 being less potent than the others (Fig. 3B).
Reference: Mol Cancer Ther. 2011 Aug; 10(8): 1490–1499. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155218/
In vivo activity:
Following i.v. administration of Genz-644282 (2 mg/kg) to nu/nu mice, the mean blood clearance, volume of distribution, and terminal half-life were 21.8 mL/min/kg, 5.44 L/kg, and 5.14 hours, respectively. An i.v. injection of Genz-644282 (2 mg/kg) to nu/nu mice bearing NCI-H460 human tumor xenografts resulted in plasma PK parameters of 104 mL/min/kg mean clearance, a 49.3-L/kg volume of distribution, and terminal half-life of 8.14 hours. The mean area under the curve (AUC) in tumor tissues (9,690 ng·h/mL) was approximately 30-fold higher than that observed in plasma (319 ng·h/mL), showing that Genz-644282 has a high penetration into tumor tissue in the xenograft model. For an analysis of the PK/PD relationship of Genz-644282, this study compared the exponential growth of tumors in control mice with tumor growth in the Genz-644282–treated mice. The growth decreased by a factor proportional to drug concentration. The estimated average tumor concentration of Genz-644282 at steady state ranged from 130 to 519 nmol/L, or 24- to 96-fold higher than the in vitro IC90 (5.4 nmol/L), thus predicting that the tumor would be responsive to treatment.
Reference: Clin Cancer Res. 2011 May 1;17(9):2777-87. https://clincancerres.aacrjournals.org/content/17/9/2777.long
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
2.1 |
3.97 |
| DMSO:PBS (pH 7.2) (1:20) |
0.0 |
0.08 |
| DMF |
0.5 |
0.96 |
| Ethanol |
0.2 |
0.38 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
521.44
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Sooryakumar D, Dexheimer TS, Teicher BA, Pommier Y. Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I inhibitor Genz-644282. Mol Cancer Ther. 2011 Aug;10(8):1490-9. doi: 10.1158/1535-7163.MCT-10-1043. Epub 2011 Jun 2. PMID: 21636699; PMCID: PMC3155218.
2. Kurtzberg LS, Roth S, Krumbholz R, Crawford J, Bormann C, Dunham S, Yao M, Rouleau C, Bagley RG, Yu XJ, Wang F, Schmid SM, Lavoie EJ, Teicher BA. Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment. Clin Cancer Res. 2011 May 1;17(9):2777-87. doi: 10.1158/1078-0432.CCR-10-0542. Epub 2011 Mar 17. PMID: 21415217.
3. Kurtzberg LS, Roth S, Krumbholz R, Crawford J, Bormann C, Dunham S, Yao M, Rouleau C, Bagley RG, Yu XJ, Wang F, Schmid SM, Lavoie EJ, Teicher BA. Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment. Clin Cancer Res. 2011 May 1;17(9):2777-87. doi: 10.1158/1078-0432.CCR-10-0542. Epub 2011 Mar 17. PMID: 21415217.
In vitro protocol:
1. Sooryakumar D, Dexheimer TS, Teicher BA, Pommier Y. Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I inhibitor Genz-644282. Mol Cancer Ther. 2011 Aug;10(8):1490-9. doi: 10.1158/1535-7163.MCT-10-1043. Epub 2011 Jun 2. PMID: 21636699; PMCID: PMC3155218.
2. Kurtzberg LS, Roth S, Krumbholz R, Crawford J, Bormann C, Dunham S, Yao M, Rouleau C, Bagley RG, Yu XJ, Wang F, Schmid SM, Lavoie EJ, Teicher BA. Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment. Clin Cancer Res. 2011 May 1;17(9):2777-87. doi: 10.1158/1078-0432.CCR-10-0542. Epub 2011 Mar 17. PMID: 21415217.
In vivo protocol:
1. Kurtzberg LS, Roth S, Krumbholz R, Crawford J, Bormann C, Dunham S, Yao M, Rouleau C, Bagley RG, Yu XJ, Wang F, Schmid SM, Lavoie EJ, Teicher BA. Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment. Clin Cancer Res. 2011 May 1;17(9):2777-87. doi: 10.1158/1078-0432.CCR-10-0542. Epub 2011 Mar 17. PMID: 21415217.
1: Sooryakumar D, Dexheimer TS, Teicher BA, Pommier Y. Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I inhibitor Genz-644282. Mol Cancer Ther. 2011 Aug;10(8):1490-9. Epub 2011 Jun 2. PubMed PMID: 21636699; PubMed Central PMCID: PMC3155218.
2: Houghton PJ, Lock R, Carol H, Morton CL, Gorlick R, Anders Kolb E, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups CA, Zhang MX, Madden SL, Teicher BA, Smith MA. Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2011 May 5. doi: 10.1002/pbc.23016. [Epub ahead of print] PubMed PMID: 21548007; PubMed Central PMCID: PMC3154998.
3: Kurtzberg LS, Roth S, Krumbholz R, Crawford J, Bormann C, Dunham S, Yao M, Rouleau C, Bagley RG, Yu XJ, Wang F, Schmid SM, Lavoie EJ, Teicher BA. Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment. Clin Cancer Res. 2011 May 1;17(9):2777-87. Epub 2011 Mar 17. PubMed PMID: 21415217.
