1. Protein Tyrosine Kinase/RTK
  2. Bcr-Abl
    FLT3
    Src

DCC-2036 (Synonyms: Rebastinib)

Cat. No.: HY-13024 Purity: 95.32%
Data Sheet SDS Handling Instructions

DCC-2036 is a conformational control Bcr-Abl inhibitor for Abl1WT and Abl1T315I with IC50 of 0.8 nM and 4 nM, also inhibits SRC, KDR, FLT3, and Tie-2, and low activity to seen towards c-Kit.

For research use only. We do not sell to patients.
DCC-2036 Chemical Structure

DCC-2036 Chemical Structure

CAS No. : 1020172-07-9

Size Price Stock Quantity
10 mM * 1 mL in DMSO $110 In-stock
5 mg $90 In-stock
10 mg $150 In-stock
50 mg $600 In-stock
100 mg   Get quote  
200 mg   Get quote  

* Please select Quantity before adding items.

  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

DCC-2036 is a conformational control Bcr-Abl inhibitor for Abl1WT and Abl1T315I with IC50 of 0.8 nM and 4 nM, also inhibits SRC, KDR, FLT3, and Tie-2, and low activity to seen towards c-Kit.

IC50 & Target

IC50: 0.75±0.11 nM (ABL1WT), 2±0.3 nM (FLT3), 4±0.3 nM (KDR), 6±0.3 nM (TIE2), 34±6 nM (SRC)[1]

In Vitro

DCC-2036 inhibits ABL1native and the gatekeeper mutant ABL1T315I with IC50 of 0.8 nM and 4 nM, respectively. DCC-2036 potently (IC50 0.82 nM) inhibits u-ABL1native, which is thought to exist predominantly in the inactive type II conformation. In addition, DCC-2036 also strongly inhibits p-ABL1native (IC50 2 nM), which more readily adopts an active, Type I conformation. More significantly, DCC-2036 potently inhibits both u-ABL1T315I (IC50 5 nM) and p-ABL1T315I (IC50 4 nM), both of which exist predominately in the Type I conformation due to stabilization of an activating hydrophobic spine by the T315I mutation. DCC-2036 also potently inhibits ABL1H396P (IC50 1.4 nM), which, like ABL1T315I, is predisposed to exist predominately in a Type I activated conformation due to the restricted backbone torsional angles imposed by the mutant Pro396. In addition to ABL1, DCC-2036 also inhibits the SRC family kinases LYN, SRC, FGR, and HCK, and PDGFRα, and PDGFRβ with IC50 of 29±1, 34±6, 38±1, 40±1, 70±10 and 113±10 nM, respectively. Notably, DCC-2036 spared c-KIT (IC50 481 nM). DCC-2036 effectively inhibits the proliferation of Ba/F3 cells expressing native BCR-ABL1native (IC50 5.4 nM). DCC-2036 also inhibits proliferation of the Ph+ cell line K562 (IC50 5.5 nM). DCC-2036 also inhibits proliferation of several common TKI-resistant mutants of BCR-ABL1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T, at IC50s ranging from 6-150 nM. DCC-2036 effectively inhibits autophosphorylation of BCR-ABL1native (IC50 29 nM) and BCR-ABL1T315I (IC50 18 nM), as well as the phosphorylation of STAT5 in both cell lines (IC50 28 nM and 13 nM, respectively)[1].

In Vivo

A single oral dose of DCC-2036 at 100 mg/kg afforded circulating plasma levels that exceeded 12 μM for up to 24 hours (data not shown), and effectively inhibited BCR-ABL1 signaling for up to 8 hours in Ba/F3-BCR-ABL1T315I leukemia cells isolated from BM and spleen of tumor-bearing mice, as assessed by intracellular flow cytometric staining for phospho-STAT5 and immunoblotting of tissue extracts for phospho-BCR-ABL1 and phospho-STAT5. Treatment of mice bearing Ba/F3-BCR-ABL1T315I leukemia cells with DCC-2036 at 100 mg/kg once daily by oral gavage significantly prolonged their survival, while imatinib at 100 mg/kg twice daily is ineffective. In this aggressive allograft model, DCC-2036 is as effective for treatment of BCR-ABLT315I leukemia as imatinib at 100 mg/kg twice daily is for treatment of BCR-ABL1native leukemia, and reduced the leukemia cell burden in the spleens of treated mice[1].

Clinical Trial
View MoreCollapse
References
Preparing Stock Solutions
Concentration Volume Mass 1 mg 5 mg 10 mg
1 mM 1.8064 mL 9.0320 mL 18.0639 mL
5 mM 0.3613 mL 1.8064 mL 3.6128 mL
10 mM 0.1806 mL 0.9032 mL 1.8064 mL
Please refer to the solubility information to select the appropriate solvent.
Kinase Assay
[1]

Peripheral blood blasts from a patient with relapsed and refractory Ph+ B-ALL and detectable T315I mutation (allele frequency 40%) are incubated overnight (initial cell viability >90%) in IMDM supplemented with 100 μM 2-mecaptoethanol and 0.5% BSA, and either without drug or with Imatinib (1 μM) or DCC-2036 (50, 200, and 1000 nM). After incubation, cells are lysed and protein extracts subjected to immunoblot analysis as described above. Peripheral blood mononuclear cells (7.5×105) from a patient with chronic phase CML and L298V mutation are incubated in varying concentrations of DCC-2036 or DMSO for 3h, followed by lysis and immunoblot analysis[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

DCC-2036 is dissolved in DMSO and stored, and then diluted with appropriate medium before use[1].

Ba/F3 cells (3×103 cells/well) or primary Ph+ leukemia cells (5×104 cells/well) are plated in triplicate in 96-well plates containing test compounds (e.g., DCC-2036). After 72h, viable cells are quantified by resazurin or MTT assay. Results represent an average of at least three independent experiments[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

DCC-2036 is prepared in 0.5% CMC/1% Tween-80 (Mice)[1].

Mice[1]
Ba/F3 cells (1×106) transformed to interleukin-3 independence by transduction with either BCR-ABL1native or BCR-ABL1T315I retrovirus are injected intravenously into syngeneic Balb/c recipients. Beginning day 3 post-injection, mice are treated with Imatinib (100 mg/kg in water twice daily via oral gavage) or with DCC-2036 (100 mg/kg in 0.5% CMC/1% Tween-80, once daily via oral gavage) or with vehicle (0.5% CMC/1% Tween-80) alone. For induction of CML-like leukemia, bone marrow (BM) from male Balb/c donor mice is harvested 4d after intravenous administration of 150 mg/kg 5-fluorouracil (5-FU), transduced with BCR-ABL1T315I retrovirus, and 5×105 cells injected intravenously into sublethally irradiated (400 cGy) Balb/c recipients. Beginning at d5 post-transplant, cohorts are treated once daily by oral gavage with vehicle alone, or DCC-2036 at 100 mg/kg. For induction of B-cell acute lymphoblastic leukemia, BM from donors not pretreated with 5-FU is transduced once with BCR-ABL1T315I retrovirus and 1×106 cells injected into sublethally irradiated Balb/c recipients. Beginning at d8 post-transplant, cohorts are treated twice daily by oral gavage with vehicle alone, with DCC-2036 at 60 mg/kg, with Imatinib at 100 mg/kg (in water), or with Dasatinib at 10 mg/kg (in 80 mM citric acid pH 3.1). MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

553.59

Formula

C₃₀H₂₈FN₇O₃

CAS No.

1020172-07-9

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Inquiry Online

Your information is safe with us. * Required Fields.

Product name

 

Salutation

Applicant name *

 

Email address *

Phone number

 

Organization name *

Country *

 

Requested quantity *

Remarks

Bulk Inquiry

Inquiry Information

Product Name:
DCC-2036
Cat. No.:
HY-13024
Quantity: