CX-5461 化学構造
分子量: 513.61

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Quality Control & MSDS

製品説明

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    DNA/RNA Synthesis製品生物活性の比較
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製品の説明

生物活性

製品説明 CX-5461は、HCT-116独房で142nMでIC50でリボソームRNA(rRNA)のPol I-driven書換えを選択的に禁止します。
ターゲット Pol I HCT-116 A375 MIA PaCa-2
IC50 142 nM 167 nM (ED50) 58 nM (ED50) 74 nM (ED50) [1]
In vitro試験 CX-5461 is found to selectively inhibit rRNA synthesis (Pol I IC50=142 nM; Pol II IC50 > 25 μM; selectivity ~200-fold) in the HCT-116 cells. Selective inhibition of rRNA synthesis by CX-5461 is confirmed in two other human solid tumor cell lines; melanoma A375 (Pol I IC50 = 113 nM; Pol II IC50 > 25 μM) and pancreatic carcinoma MIA PaCa-2 (Pol I IC50=54 nM; Pol II IC50 ~25 mM). CX-5461 possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation. CX-5461 exhibits broad antiproliferative potency in a panel of cancer cell lines in human cancer cell lines, but has minimal effect on viability of nontransformed human cells. The median EC50 across all tested cell lines is 147 nM, yet all normal cell lines have EC50 values of approximately 5, 000 nM. Evaluation of the antiproliferative dose response for HCT-116, A375, and MIA PaCa-2 cell lines yield EC50 values of 167, 58, and 74 nM. CX-5461 induces autophagy and senescence in solid tumor cancer cells, rather than apoptosis, through a p53-independent process. [1]
In vivo試験 CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. CX-5461 demonstrates significant MIA PaCa-2 TGI with TGI equal to 69% on day 31, comparable to that of gemcitabine (63% TGI). Gemcitabine is a positive control which is administered intraperitoneally once every 3 days at 120 mg/kg. Likewise, CX- 5461 demonstrates significant A375 TGI with TGI equal to 79% on day 32. [1]
臨床試験
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Pol I and Pol II Transcription Assay Two short-lived RNA transcripts (half-lives ~20-30 minutes), one produced by Pol I and another by Pol II, are quantitated by qRT-PCR as a measure of CX-5461-related effects on transcription. The 45S pre-rRNA served as the Pol I transcript and the mRNA for the protooncogene c-myc served as the comparator Pol II transcript. Both Pol I and Pol II transcription are known to be affected by general cellular stress. To minimize the potential effects of such stress, cells are exposed to test agents for only a short period of time (2 hours). This is sufficient time for these transcripts to be reduced by greater than 90% if CX-5461 affects their synthesis.

細胞アッセイ: [1]

細胞株 panel of cancer and normal cell lines
濃度 0-2 μM
反応時間 96 hours
実験の流れ Cells are plated on 96-well plates and treated the next day with dose response of CX-5461 for 96 hours. Cell viability is determined using Alamar Blue and CyQUANT assays

動物実験: [1]

動物モデル 5 × 106 MIA Paca-2 and A375 cancer cells are subcutaneously inoculated in the right flank of 5- to 6- week-old female athymic mice
製剤 CX-5461 is dissolved in 50 mM NaH2PO4 (pH 4.5).
投薬量 50 mg/kg
投与方法 CX-5461 is administered orally once daily or every 3 days.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download CX-5461 SDF
分子量 513.61
化学式

C27H27N7O2S

CAS No. 1138549-36-6
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMF 3 mg/mL warmed (5.84 mM)
DMSO 0.02 mg/mL (0.03 mM)
<1 mg/mL (<1 mM)
In vivo
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 5H-Benzothiazolo[3,2-a][1,8]naphthyridine-6-carboxamide, 2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-N-[(5-methyl-2-pyrazinyl)methyl]-5-oxo-

カスタマーフィードバック (2)


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Rating
Source , , Oncogene, 2015, 10.1038/onc.2015.147. CX-5461 purchased from Selleck
Method Western Blot
Cell Lines HCT116, HepG2, MCF7 & LoVo cells
Concentrations 1 µM
Incubation Time 12 h
Results CX-5461 caused a reduction in the 45S rRNA expression as evaluated by real-time RT–PCR in all the four cell lines.

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Rating
Source PLoS One, 2014, 9(8), e104364. CX-5461 purchased from Selleck
Method Immunocytochemistry
Cell Lines Primary hippocampal neurons
Concentrations 200 nM
Incubation Time 1, 3 h
Results CX-5461 has also been shown to cause rapid nucleolar disruption in cell lines. Using cultured hippocampal neurons it found that a 3 h application of 200 nM CX5461 was sufficient to cause fibrillarin to concentrate into small punctate domains indicative of nucleolar fragmentation.

文献中の引用 (4)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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