Rebastinib (DCC-2036)

Catalog No.S2634

Rebastinib (DCC-2036) Chemical Structure

Molecular Weight(MW): 553.59

Rebastinib (DCC-2036) is a conformational control Bcr-Abl inhibitor for Abl1(WT) and Abl1(T315I) with IC50 of 0.8 nM and 4 nM, also inhibits SRC, LYN, FGR, HCK, KDR, FLT3, and Tie-2, and low activity to seen towards c-Kit. Phase 1.

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2 Customer Reviews

  • BaF3-T674I cells were exposed to the indicated concentrations of DCC-2036, imatinib or sorafenib for 36 h, the phosphorylated PDGFRα and total PDGFRα were analyzed by immunoblotting. Imatinib was used for comparison.

    PLoS One 2013 8, e73059. Rebastinib (DCC-2036) purchased from Selleck.

    Immunohistochemical analysis of Ki67 in xenograft tissues from mice. Hematoxylin and eosin (H&E)-stained serial sections of the same xenografts are presented.

    PLoS One 2013 8, e73059. Rebastinib (DCC-2036) purchased from Selleck.

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Biological Activity

Description Rebastinib (DCC-2036) is a conformational control Bcr-Abl inhibitor for Abl1(WT) and Abl1(T315I) with IC50 of 0.8 nM and 4 nM, also inhibits SRC, LYN, FGR, HCK, KDR, FLT3, and Tie-2, and low activity to seen towards c-Kit. Phase 1.
Features A conformational control inhibitor of Abl1 and T315I Abl1.
Targets
u-Abl1 (native) [1]
(Cell-free assay)
Abl1 (H396P) [1]
(Cell-free assay)
p-Abl1 (native) [1]
(Cell-free assay)
FLT3 [1]
(Cell-free assay)
p-Abl1 (T315I) [1]
(Cell-free assay)
0.75 nM 1.4 nM 2 nM 2 nM 4 nM
In vitro

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 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]

Protocol

Kinase Assay:[1]
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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.
Cell Research:[1]
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  • Cell lines: Ba/F3 cells and primary Ph+ leukemia cells
  • Concentrations: 0-10 μM
  • Incubation Time: 72 hours
  • Method: 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
    (Only for Reference)
Animal Research:[1]
+ Expand
  • Animal Models: 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.
  • Formulation: DCC-2036 is dissolved in 0.5% CMC/1% Tween-80.
  • Dosages: ≤100 mg/kg
  • Administration: Administered via p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 111 mg/mL (200.5 mM)
Ethanol 16 mg/mL (28.9 mM)
Water Insoluble
In vivo Add solvents individually and in order:
0.5% CMC+0.25% Tween 80
16 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.

Chemical Information

Molecular Weight 553.59
Formula

C30H28FN7O3

CAS No. 1020172-07-9
Storage powder
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02824575 Recruiting Breast Cancer|Breast Adenocarcinoma|Human Epidermal Growth Factor 2 Negative Carcinoma of Breast|Recurrent Breast Carcinoma|Stage IV Breast Cancer Montefiore Medical Center|Deciphera Pharmaceuticals LLC|Albert Einstein College of Medicine of Yeshiva University July 2016 Phase 1
NCT00827138 Completed Chronic Myeloid Leukemia Deciphera Pharmaceuticals LLC March 2009 Phase 1

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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID