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Genz-644282 (Synonyms: Genz644282;Genz 644282)

Catalog No.GC15853

An inhibitor of topoisomerase I

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Genz-644282 Chemical Structure

Cas No.: 529488-28-6

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5mg
$81.00
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10mg
$157.00
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25mg
$228.00
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50mg
$342.00
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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Cell experiment:

Twenty-nine established human tumor cell lines are exposed to a concentration range of Genz-644282 in two-four independent experiments. Human tumor cell lines representing a range of histology and potential resistance mechanisms includ 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 cancer, ACHN, 769-P, A-498, A-704, SW156, Caki-2 and TK-10 renal cancers and OVCAR-4 and OVCAR-5 ovarian cancers. Cells are plated at 4 × 103/well in 96-well tissue culture plates in 100 µL RPMI medium supplemented with 5% FBS and 12 concentrations of Genz-644282 from 0.1 nM to 10 µM, with each concentration tested in triplicate. Plates are incubated overnight at 37ºC in humidified air with 5% CO2. Plates are incubated with Genz-644282 at 37ºC with humidified air/5% CO2 for 72 hrs. After the incubation period, the test plates are read utilizing Cell Titer-Glo Luminescent Cell Viability Assay. Luminescence is measured with a Synergy HT plate reader utilizing the associated ineticalc software, Version #3.4. Luminescence data are converted to growth fraction by comparison to the luminescence for the untreated control for each cell line and IC50 and IC90 values determined from the graphical data. Each cell line is tested in t least two independent experiments[1].

Animal experiment:

Nu/nu mice are implanted subcutaneously with a 4 mm3 tumor fragment, and treatments are initiated when tumors reach 200 mm3. Compounds are prepared freshly prior to injection, with Genz-644282 is formulated in M/6 lactate, irinotecan in D5W (5% Dextrose, aqueous), gemcitabine in saline, and docetaxel in ethanol, Cremophor EL and saline. Genz-644282 is compared with irinotecan in experiments with the human HCT-116, HT-29, HCT-15 and DLD-1 colon carcinoma and 786-O renal cell carcinoma xenografts. Irinotecan is administered at 60 mg/kg/day by IV injection every fourth day for three injections. Genz-644282 is compared with docetaxel in the human CIH460 non-small cell lung carcinoma xenograft. Docetaxel is administered at 12, 16 or 20 mg/kg/day by IV injection on alternate days for three injections. Genz-644282 is compared with dacarbazine in the human LOX-IMVI melanoma xenograft. Dacarbazine is administered at 90 mg/kg/day by IP injection once daily for 5 days. Genz-644282 is administered at 1, 1.36, 1.7, 2.7 or 4.1 mg/kg/day by IV on alternate days 3-times per week for 2 weeks in all in vivo experiments[1].

References:

[1]. Kurtzberg LS, et al. Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment. Clin Cancer Res. 2011 May 1;17(9):2777-87.
[2]. Houghton PJ, et al. Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb;58(2):200-9.
[3]. Sooryakumar D, et al. Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I inhibitor Genz-644282. Mol Cancer Ther. 2011 Aug;10(8):1490-9.

Background

Description: IC50 Value: 1.2 nM [1] Genz-644282 [8,9-dimethoxy-5-(2-N-methylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one] has emerged as a promising candidate of non-Camptothecin topoisomerase I inhibitor for antitumor agents. in vitro: Genz-644282 demonstrated potent cytotoxic activity with a median IC(50) of 1.2?nM (range 0.2-21.9?nM) [1]. Limited cross-resistance to Genz-644282 was also found in the Top1 knockdown colon cancer (HCT116) and breast cancer (MCF7) cell lines and in human adenocarcinoma cells (KB31/KBV1) that overexpress (P-glycoprotein, ABCB1), a member of the ATP-binding cassette family of cell surface transport proteins known to confer MDR [3]. in vivo: Genz-644282 at its MTD (4mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid tumor models. At 2mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models relatively insensitive to topotecan, but there were no objective responses at 1mg/kg [1]. Genz-644282 was tolerated at doses up to 4 mg/kg when administered intravenously on alternate days, and the compound was active at doses from 1 to 4 mg/kg. The efficacy of Genz-644282 was compared with irinotecan in 4 human colon carcinoma xenograft models. In the human HCT-116 colon cancer xenograft, TGD values were 14 days for irinotecan (60 mg/kg) and 34 days for Genz-644282 (2.7 mg/kg), giving maximum test to control ratios (T/Cs) of 23.7% and 16.8%, respectively [2]. Clinical trial: Dose-Escalation Study to Assess the Safety and Tolerability of Genz-644282 in Patients With Solid Tumors. Phase 1

Chemical Properties

Cas No. 529488-28-6 SDF
Synonyms Genz644282;Genz 644282
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
Canonical SMILES O=C1N(C([H])([H])C([H])([H])N([H])C([H])([H])[H])C(C(C(N=C2[H])=C3[H])=C([H])C4=C3OC([H])([H])O4)=C2C(C1=C5[H])=C([H])C(OC([H])([H])[H])=C5OC([H])([H])[H]
Formula C22H21N3O5 M.Wt 407.42
Solubility DMF: 0.5 mg/ml,DMSO: 0.5 mg/ml,DMSO:PBS (pH 7.2) (1:20): 0.04 mg/ml,Ethanol: 0.2 mg/ml Storage 4°C, protect from light
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 2.4545 mL 12.2723 mL 24.5447 mL
5 mM 0.4909 mL 2.4545 mL 4.9089 mL
10 mM 0.2454 mL 1.2272 mL 2.4545 mL
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