DCC-2036 (Rebastinib)

DCC-2036 (Rebastinib)は一種のBcr-Abl阻害剤で、Abl1(WT)とAbl1(T315I)に作用する時のIC50値が0.8 nMと4 nMです。DCC-2036 (Rebastinib)はSRC、LYN、FGR、HCK、KDR、FLT3とTie-2も抑制しますが、c-Kitに低い抑制活性を表します。臨床1期。

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DCC-2036 (Rebastinib) 化学構造
分子量: 553.59

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製品説明

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    Bcr-Abl製品生物活性の比較
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  • Combination Therapy
    併用療法
  • DCC-2036 (Rebastinib)のメカニズム

製品の説明

生物活性

製品説明 DCC-2036 (Rebastinib)は一種のBcr-Abl阻害剤で、Abl1(WT)とAbl1(T315I)に作用する時のIC50値が0.8 nMと4 nMです。DCC-2036 (Rebastinib)はSRC、LYN、FGR、HCK、KDR、FLT3とTie-2も抑制しますが、c-Kitに低い抑制活性を表します。臨床1期。
ターゲット u-Abl1native p-Abl1native Abl1H396P u-Abl1T315I p-Abl1T315I
IC50 0.8 nM 2 nM 1.4 nM 5 nM 4 nM [1]
In vitro試験 DCC-2036 shows the potent inhibitory activities against purified native Abl1 in unphosphorylated (u-Abl1native) and phosphorylated (p-Abl1native) forms, unphosphorylated and phosphorylated gatekeeper mutant Abl1T315I, and the activation loop mutant Abl1H396P in a non-ATP-competitive manner with IC50 of 0.8 nM, 2 nM, 1.4 nM, 5 nM, and 4 nM, respectively. Moreover, DCC-2036 also inhibits the Src family kinases Src, LYN, FGR, and HCK, and the receptor TKs KDR, FLT3, and TIE2 with IC50 of 34 nM, 29 nM, 38 nM, 40 nM, 4 nM, 2 nM and 6 nM, respectively. [1] DCC-2036 shows the anti-proliferative activities against Ba/F3 cells expressing native or mutant Bcr-Abl1 with IC50 ranging from 2 nM to 150 nM. In addition, DCC-2036 also inhibits proliferation of the Ph+ cell line K562 (IC50 5.5 nM), and induces apoptosis in both Bcr-Abl1-expressing Ba/F3 and K562 cells potently. [1] A recent study shows that DCC-2036 shows the selectivity for growth inhibition of Bcr-Abl-positive cells by its marked inhibition of CML cell lines compared to non-CML leukemia lines. [2]
In vivo試験 In a mouse allograft model bearing Ba/F3-Bcr-Abl1T315I leukemia cells, DCC-2036 treatment by oral gavage at 100 mg/kg once daily effectively inhibits Bcr-Abl1 signaling and significantly prolongs mouse survival. [1]
臨床試験 DCC-2036 is currently in Phase I/II clinical trials in patients with chronic myeloid leukemia.
特集 A conformational control inhibitor of Abl1 and T315I Abl1.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Assay of Abl1 kinase isoforms and determination of inhibitor potency Activity of u-Abl1native is determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system. In this assay, the oxidation of NADH (measured as a decreased A340nm) is continuously monitored spectrophotometrically. The final reaction mixture (100 μL, in a 384-well Corning plate) is prepared as follows: An Abl1 kinase/coupled assay components mixture is prepared containing u-Abl1 kinase (1 nM), Abltide (EAIYAAPFAKKK, 0.2 mM), MgCl2 (9 mM), pyruvate kinase (~ 4 units), lactate dehydrogenase (~ 0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris containing 0.1 % octyl-glucoside and 1 % DMSO, pH 7.5. Separately, an inhibitor mixture is prepared containing DCC-2036 serially diluted 3-fold in DMSO followed by dilution into buffer composed of 180 mM Tris, pH 7.5, containing MgCl2 (18 mM) and 0.2 % octyl-glucoside. Fifty μL of the inhibitor mixture is mixed with 50 μL of the above Abl1 kinase/coupled assay components mixture, which is then incubated at 30 °C for 2 hours before 2 μL of 25 mM ATP (500 μM, final) is added to start the reaction. The reaction is recorded every 2 minutes for 2.5 hours at 30 °C on a Polarstar Optima or Synergy2 plate reader. Reaction rate (slope) is calculated using the 1 to 2 hour time frame with reader's software. Percent inhibition is obtained by comparison of reaction rate with that of a DMSO control. IC50 values are calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using GraphPad Prism. The kinase assay for Abl1T315I, p-Abl1native or Abl1H396P is assayed the same as above except that 2.2 nM Abl1T315I, 1 nM p-Abl1 native or 1.3 nM Abl1H396P is used. The above assay format is also used for kinases other than Abl1 with the exception of TIE2, for which a fluorescence polarization/Transcreener format is used. The assay conditions are the same as described above except that PolyE4Y (final 1 mg/mL) is used as the substrate and one hour preincubation is used.

細胞アッセイ: [1]

細胞株 Ba/F3 cells and primary Ph+ leukemia cells
濃度 0-10 μM
反応時間 72 hours
実験の流れ Ba/F3 cells or primary Ph+ leukemia cells are plated in triplicate in 96-well plates containing test compounds. After 72 hours, viable cells are quantified by Resazurin or MTT assay. Cells are diluted in medium to be added to each well of a 96-well tissue culture-treated plate. All cells are incubated overnight and maintained in a humidified atmosphere at 37 °C and 5% CO2. Cells are treated the following day. Serum-free medium is used during treatment with DCC-2036. MTT is used to assess the viability of cells following treatment. Aliquots of 20 mL of stock MTT solution are added to each well containing 200 mL of medium (10% final solution) and incubated with the cells for 2 hours. Following incubation the medium is removed and 200 mL of dimethylsulfoxide added to solubilize the formazan crystals. The absorbance is read on the plate reader at 550 and 690 nm. A subtraction analysis of the dual wavelength is performed (D550 to D690) to increase accuracy of the measuremen

動物実験: [1]

動物モデル Ba/F3 cells transformed to interleukin-3 independence by transduction with either Bcr-Abl1native or Bcr-Abl1T315I retrovirus are injected intravenously into syngeneic Balb/c mice.
製剤 DCC-2036 is dissolved in 0.5% CMC/1% Tween-80.
投薬量 ≤100 mg/kg
投与方法 Administered via p.o.

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 DCC-2036 (Rebastinib) SDF
分子量 553.59
化学式

C30H28FN7O3

CAS No. 1020172-07-9
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 111 mg/mL (200.5 mM)
Ethanol 16 mg/mL (28.9 mM)
Water <1 mg/mL
In vivo 0.5% CMC+0.25% Tween 80 16 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 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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