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Rebastinib (formerly also known as DCC-2036), a novel, potent and orally bioavailable small-molecule inhibitor of multiple tyrosine kinases with potential antineoplastic activity, is a conformational control Bcr-Abl inhibitor for Abl1(WT) and Abl1(T315I) with IC50s of 0.8 nM and 4 nM. It also inhibits other kinases such as SRC, LYN, FGR, HCK, KDR, FLT3, and Tie-2, and has low activity towards c-Kit. DCC-2036 inhibits ABL1 through forcing the kinase domains into inhibitor-bound, inactive Type II conformations. In cellular assay, DCC-2036 inhibits the proliferation of Ba/F3 and K562 cells with IC50 values of 5.4nM and 5.5nM, respectively.
| ln Vitro |
It is believed that u-ABL1native (IC50 0.82 nM) mostly exists in the inactive type II conformation, and rebastinib potently inhibits it. Furthermore, p-ABL1native (IC50 2 nM) is significantly inhibited by ribatinib, leading to a higher likelihood of the protein adopting the active form I mutant [1]. Given that the T315I mutation stabilizes the activated hydrophobic spine, u-ABL1T315I (IC50 5 nM) and p-ABL1T315I (IC50 4 nM) primarily occur in the I-type conformation and are efficiently inhibited by ribazinib [1]. Furthermore, ribatinib inhibits PDGFRα and PDGFRβ, as well as the SRC family kinases LYN, SRC, FGR, and HCK, with IC50 values of 29±1, 34±6, 38±1, 40±1, 70±10, and 113 nM, respectively, in addition to ABL1. Noticeably, c-KIT (IC50 481 nM) was unaffected by ribatinib [1]. When Ba/F3 cells express natural BCR-ABL1, rebastinib substantially inhibits their growth (IC50 5.4 nM). Furthermore, the Ph+ cell line K562 (IC50 5.5 nM) is not able to proliferate when treated with rebastinib]1. Additionally, with an IC50 ranging from 6-150 nM, rebastinib inhibits the proliferation of several common TKI-resistant mutations of BCR-ABL1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T. Resistant to autophosphorylation, rebastinib potently suppresses the phosphorylation of STAT5 in both cell lines (IC50 28 nM and 13 nM, respectively), as well as BCR-ABL1native (IC50 29 nM) and BCR-ABL1T315I (IC50 18 nM) [1].
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| ln Vivo |
Rebastinib (DCC-2036; oral; 100 mg/kg) can effectively block BCR-ABL1 signaling in Ba/F3-BCR-ABL1T315I leukemia cells isolated from BM and spleen of tumor-bearing mice for up to 8 hours, and a single dose can result in circulating plasma levels that surpass 12 μM for up to 24 hours[1]. Rebastinib at 100 mg/kg once daily by oral gavage dramatically increased the survival of mice harboring Ba/F3-BCR-ABL1T315I leukemia cells, although STI571 at 100 mg/kg twice daily is ineffective[1]. Rebastinib lowers the leukemia cell burden in the spleens of treated mice and is equally effective in treating BCR-ABLT315I leukemia in this aggressive allograft model as STI571 at 100 mg/kg twice day in BCR-ABL1native leukemia[1].
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| References |
[1]. Chan WW, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011, 19(4), 556-568
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| Molecular Formula |
C30H28FN7O3
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| Molecular Weight |
553.59
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| CAS # |
1020172-07-9
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| Related CAS # |
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| SMILES |
O=C(NC1=CC=C(OC2=CC(C(NC)=O)=NC=C2)C=C1F)NC3=CC(C(C)(C)C)=NN3C4=CC=C5N=CC=CC5=C4
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| InChi Key |
WVXNSAVVKYZVOE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H28FN7O3/c1-30(2,3)26-17-27(38(37-26)19-7-9-23-18(14-19)6-5-12-33-23)36-29(40)35-24-10-8-20(15-22(24)31)41-21-11-13-34-25(16-21)28(39)32-4/h5-17H,1-4H3,(H,32,39)(H2,35,36,40)
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| Chemical Name |
N-[3-tert-Butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]-N'-[2-fluoro-4-[(2-(methylcarbamoyl)pyridin-4-yl)oxy]phenyl]urea
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| Synonyms |
DCC-2036; DCC 2036; DCC2036; Rebastinib.
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.76 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.76 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 0.5% CMC+0.25% Tween 80:16 mg/mL |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02824575 | Terminated | Drug: Rebastinib Drug: Paclitaxel |
Breast Cancer Breast Adenocarcinoma |
Montefiore Medical Center | July 2016 | Phase 1 |
| NCT03717415 | Completed | Drug: rebastinib Drug: Carboplatin |
Locally Advanced or Metastatic Solid Tumor |
Deciphera Pharmaceuticals LLC | January 2, 2019 | Phase 1 Phase 2 |
| NCT03601897 | Completed | Drug: rebastinib Drug: Paclitaxel |
Locally Advanced or Metastatic Solid Tumor |
Deciphera Pharmaceuticals LLC | October 25, 2018 | Phase 1 Phase 2 |
| NCT00827138 | Completed | Drug: DCC-2036 | Chronic Myeloid Leukemia | Deciphera Pharmaceuticals LLC | March 2009 | Phase 1 |
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