Flavopiridol (Alvocidib) HCl

Flavopiridol (Alvocidib) HClは、サイクリン依存的なkianses(CDK)を妨げるために、ATPと争いまして、 CDK1, CDK2, CDK4、CDK6 に作用すると、IC50が40 nMになり、CDK7に作用すると、IC50が 300 nMになる。

目録号S2679
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Flavopiridol (Alvocidib) HCl 化学構造
分子量: 438.3

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製品情報

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製品の説明

生物活性

情報 Flavopiridol (Alvocidib) HClは、サイクリン依存的なkianses(CDK)を妨げるために、ATPと争いまして、 CDK1, CDK2, CDK4、CDK6 に作用すると、IC50が40 nMになり、CDK7に作用すると、IC50が 300 nMになる。
目標 CDK1 CDK2 CDK4 CDK6 CDK7
IC50 40 nM 40 nM 40 nM 40 nM 300 nM [1]
In vitro試験 Flavopiridol is initially found to inhibit the epidermal growth factor receptor and protein kinase A (IC50 = 21 and 122 μM). Flavopiridol is later shown to inhibit cell proliferation, at more physiologically relevant concentrations (IC50 = 66 nM) when Flavopiridol is tested in the National Cancer Institute Development Therapeutics Program panel of 60 human tumor cell lines. [1] Flavopiridol induces G1 arrest with inhibition of CDK2 and CDK4 in human breast carcinoma cells in a time and concentration dependent manner. [2] Short time treatment of Flavopiridol (~12 hours) induce apoptosis in hematopoietic cell lines including SUDHL4, SUDHL6 (B-cell lines), Jurkat and MOLT4 (T-cell lines ), and HL60 (myeloid). [3] In the clonogenic assay, Flavopiridol functions as a highly potent cytotoxic compound with a mean IC70 with 8 ng/mL in 23 human tumor models. [4] A recent study shows Flavopiridol treatment induces a substantial AKT-Ser473 phosphorylation in human glioblastoma T98G cell line. [5]
In vivo試験 At the maximal tolerated dose of 10 mg/kg/day administered p.o. on days 1-4 and 7-11, Flavopiridol effects tumor regression in PRXF1337 and tumor stasis lasting for 4 weeks in PRXF1369. [4] After treatment with 7.5 mg/kg Flavopiridol bolus intravenous (IV) or intraperitoneal on each of 5 consecutive days, 11 out of 12 advanced stage subcutaneous (s.c.) human HL-60 xenografts undergo complete regressions, and animals remain disease-free several months after one course of Flavopiridol treatment. SUDHL-4 s.c. lymphomas treated with flavopiridol at 7.5 mg/kg bolus IV for 5 days undergo either major (two out of eight mice) or complete (four out of eight mice) regression, with two animals remaining disease-free for more than 60 days. The overall growth delay is 73.2%. Daily IV or IP administration of flavopiridol results in peak plasma levels of about 7 µM, followed by a progressive decline to approximately 100 nM in 8 hours.[6]
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特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

Recombinant CDKs Kinase Reactions CDKs activities are determined in microtiter plates as follows. Forty μg Gst-Rb are mixed with different amounts of Flavopiridol and unlabeled ATP. Reactions are then started by the addition of an ammonium sulfate cut of the S100 fraction obtained from insect cells expressing recombinant human CDKs. The final reaction conditions are 10 mM MgCl2, 50 mM Tris-HCl (pH 7.5), and 1 mM DTT. The final concentration of ATP is adjusted accordingly. Radiolabeled ATP is used as a phosphoryl donor. The reaction is carried out for 2.5 minutes at 30 °C after addition of enzyme and then terminated with the addition of EDTA. The Gst-Rb is then captured with glutathione-Sepharose and the incorporated radioactivity is determined by liquid scintillation counting.

細胞アッセイ: [2]

細胞系 SUDHL4, SUDHL6, Jurkat, MOLT4, and HL60
濃度 0, 100 500, 5000 nM
処理時間 14 hours
方法 Cells grown at a density of 1 × 106 cells/mL are exposed to Flavopiridol for different concentrations and time periods. DNA is extracted. Briefly, cells are washed once with cold phosphate-buffered saline (PBS) and lysed with 3 mL lysis buffer (5 mM Tris-HCL [pH 7.5]; 20 mM EDTA; 0.5% Triton X-100) for 15 minutes at 4 °C. The chromatin of the cell lysates is isolated by centrifugation (20 minutes at 26,000g, 4 °C). The supernatants containing small DNA fragments are extracted sequentially with phenol, phenol:chloroform (1:1), and chloroform. Nucleic acids are precipitated in 0.5 M NaCl, 90% ethanol at -20 °C overnight. RNA is then digested by bovine RNAaseA (60 μg/mL). After sequential reextraction and reprecipitation, DNA is dissolved in 10 mM Tris-HCL (pH 7.5), 1 mM EDTA, 0.5% sodium dodecyl sulfate (SDS) before electrophoresis on 1.6% agarose gel.

動物実験: [4] [6]

動物モデル Human prostate cancer xenografts, PRXFI337 and PRXFI369, grown s.c. in nude mice [4] Human promyelocytic leukemia HL-60, human B-cell follicular lymphoma SUDHL-4, and acquired immunodeficiency syndrome (AIDS)-r
製剤 Water [4]; 1% DMSO [6]
投薬量 10 mg/kg/d [4]; 7.5 mg/kg/d [6]
管理 p.o.[4]; i.p. or i.v. [6]
Solubility 30% propylene glycol, 5% Tween 80, 65% D5W, 30 mg/mL
* 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.

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

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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 Flavopiridol (Alvocidib) HCl SDF
分子量 438.3
化学式

C21H20ClNO5.HCl

CAS No. 131740-09-5
保管 2年-20℃
6月-80℃in DMSO
別名 NSC 649890 HCl
溶解度 (25°C) * In vitro DMSO 88 mg/mL (200 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W, 30 mg/mL
* <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 2-(2-chlorophenyl)-5,7-dihydroxy-8-((3S,4R)-3-hydroxy-1-methylpiperidin-4-yl)-4H-chromen-4-one hydrochloride

研究分野

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Source PNAS, 2011.May, 108:8417. Flavopiridol (Alvocidib) HCl purchased from Selleck
Method Fluorescent Microscopy/Confocal Imaging
Cell Lines Tg:Pomc-Pttg embryo, Pomc-eGFP embryo
Concentrations 50 μM
Incubation Time 18-48 h
Results Although flavopiridol retarded early embryonic development before corticotroph ontogeny occurred, in vivo treatment of zebrafish embryos with R-roscovitine, olomoucine, PD-0332991, and CAY10572 starting at 18 hpf caused no apparent growth defect by 40 hpf. Strikingly, R-roscovitine-treated embryos exhibited approximately 40% reduction in pituitary POMC-eGFP expression compared with controls.

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