Rebastinib
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MedKoo CAT#: 200851

CAS#: 1020172-07-9

Description: Rebastinib, also known as DCC-2036, is an orally bioavailable small-molecule inhibitor of multiple tyrosine kinases with potential antineoplastic activity. Multitargeted tyrosine kinase inhibitor DCC-2036 binds to and inhibits the Bcr-Abl fusion oncoprotein by changing the conformation of the folded protein to disallow ligand-dependent and ligand-independent activation; in addition, this agent binds to and inhibits Src family kinases LYN, HCK and FGR and the receptor tyrosine kinases TIE-2 and VEGFR-2. Multitargeted tyrosine kinase inhibitor DCC-2036 may exhibit more potent activity against T315I Bcr-Abl gatekeeper mutant kinases than other Bcr-Abl kinase inhibitors


Chemical Structure

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Rebastinib
CAS# 1020172-07-9

Theoretical Analysis

MedKoo Cat#: 200851
Name: Rebastinib
CAS#: 1020172-07-9
Chemical Formula: C30H28FN7O3
Exact Mass: 553.22377
Molecular Weight: 553.59
Elemental Analysis: C, 65.09; H, 5.10; F, 3.43; N, 17.71; O, 8.67

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 750.0 Ready to ship
500.0mg USD 1450.0 Ready to ship
1.0g USD 2650.0 Ready to ship
2.0g USD 3850.0 Ready to ship
5.0g USD 6850.0 Ready to ship
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Synonym: DCC2036; DCC-2036; DCC 2036; Rebastinib.

IUPAC/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

InChi Key: WVXNSAVVKYZVOE-UHFFFAOYSA-N

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)

SMILES Code: 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

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Rebastinib is a Bcr-Abl inhibitor for Abl1WT and Abl1T315I with IC50s of 0.8 nM and 4 nM, respectively.
In vitro activity: The effects of rebastinib on cell infiltration and, in particular, Tie2+ macrophage infiltration were evaluated. Rebastinib significantly decreased both total and Tie2+ macrophages (Figure 3A–C) but did not significantly affect lymphoid immune cell composition (Figure S8). There was a trend toward reduction of M2-polarized macrophages (Figure 3B) and the subset of M2 macrophages expressing Tie2 (Figure S8), however this reduction did not achieve significance. In a separate analysis, multichannel Immunofluorescence (IF) staining (Iba1 for macrophages, CD31 for endothelium and Tie2) was used to specifically distinguish the Tie2+ macrophage subpopulation (Figures 3D–E) and demonstrated that the Tie2+ macrophage subpopulation was significantly decreased in response to rebastinib treatment (Figures 3D–E and Figure S9A), confirming the reduction in the Tie2+ macrophage subpopulation in response to rebastinib (Figure 3C). Reference: Mol Cancer Ther. 2017 Nov;16(11):2486-2501. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669998/
In vivo activity: To examine rebastinib inhibition of Tie2 signaling in vivo, an orthotopic mouse mammary cancer implant model in which the polyoma middle T antigen is under the control of the mouse mammary tumor virus long terminal repeat (MMTV-PyMT) was used. Rebastinib significantly reduced primary tumor growth by 75% and more importantly, when used in combination with paclitaxel, rebastinib had an additive effect in reducing tumor growth by 90% of control (Figure 2A). The data demonstrated that rebastinib treatment in PyMT (Polyoma Middle T) mammary tumors either daily, or through intermittent dosing alone or in combination with chemotherapy, reduces primary tumor volume and extends survival time. Reference: Mol Cancer Ther. 2017 Nov;16(11):2486-2501. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669998/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 54.2
DMF 30.0 54.2
Ethanol 1.0 1.8

Preparing Stock Solutions

The following data is based on the product molecular weight 553.59 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Harney AS, Karagiannis GS, Pignatelli J, Smith BD, Kadioglu E, Wise SC, Hood MM, Kaufman MD, Leary CB, Lu WP, Al-Ani G, Chen X, Entenberg D, Oktay MH, Wang Y, Chun L, De Palma M, Jones JG, Flynn DL, Condeelis JS. The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors. Mol Cancer Ther. 2017 Nov;16(11):2486-2501. doi: 10.1158/1535-7163.MCT-17-0241. Epub 2017 Aug 24. PMID: 28838996; PMCID: PMC5669998.
In vitro protocol: 1. Harney AS, Karagiannis GS, Pignatelli J, Smith BD, Kadioglu E, Wise SC, Hood MM, Kaufman MD, Leary CB, Lu WP, Al-Ani G, Chen X, Entenberg D, Oktay MH, Wang Y, Chun L, De Palma M, Jones JG, Flynn DL, Condeelis JS. The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors. Mol Cancer Ther. 2017 Nov;16(11):2486-2501. doi: 10.1158/1535-7163.MCT-17-0241. Epub 2017 Aug 24. PMID: 28838996; PMCID: PMC5669998.
In vivo protocol: 1. Harney AS, Karagiannis GS, Pignatelli J, Smith BD, Kadioglu E, Wise SC, Hood MM, Kaufman MD, Leary CB, Lu WP, Al-Ani G, Chen X, Entenberg D, Oktay MH, Wang Y, Chun L, De Palma M, Jones JG, Flynn DL, Condeelis JS. The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors. Mol Cancer Ther. 2017 Nov;16(11):2486-2501. doi: 10.1158/1535-7163.MCT-17-0241. Epub 2017 Aug 24. PMID: 28838996; PMCID: PMC5669998.

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1: O'Hare T, Zabriskie MS, Eide CA, Agarwal A, Adrian LT, You H, Corbin AS, Yang F, Press RD, Rivera VM, Toplin J, Wong S, Deininger MW, Druker BJ. The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Blood. 2011 Nov 10;118(19):5250-4. Epub 2011 Sep 8. PubMed PMID: 21908430; PubMed Central PMCID: PMC3217407.

2: Eide CA, Adrian LT, Tyner JW, Mac Partlin M, Anderson DJ, Wise SC, Smith BD, Petillo PA, Flynn DL, Deininger MW, O'Hare T, Druker BJ. The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile. Cancer Res. 2011 May 1;71(9):3189-95. Epub 2011 Apr 19. PubMed PMID: 21505103; PubMed Central PMCID: PMC3206627.

3: Chan WW, Wise SC, Kaufman MD, Ahn YM, Ensinger CL, Haack T, Hood MM, Jones J, Lord JW, Lu WP, Miller D, Patt WC, Smith BD, Petillo PA, Rutkoski TJ, Telikepalli H, Vogeti L, Yao T, Chun L, Clark R, Evangelista P, Gavrilescu LC, Lazarides K, Zaleskas VM, Stewart LJ, Van Etten RA, Flynn DL. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011 Apr 12;19(4):556-68. PubMed PMID: 21481795; PubMed Central PMCID: PMC3077923.

4: O'Hare T, Deininger MW, Eide CA, Clackson T, Druker BJ. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2011 Jan 15;17(2):212-21. Epub 2010 Nov 22. PubMed PMID: 21098337.
 



Additional Information

DCC-2036 inhibits BCR-ABL kinase, an oncogenic fusion protein kinase resulting from chromosomal translocation (Philadelphia + chromosome). BCR-ABL is causative of myeloproliferative diseases, including chronic myelogenous leukemia (CML). In preclinical studies, DCC-2036 has demonstrated potent enzymatic and cellular inhibition of BCR-ABL, the T315I gatekeeper mutant, and other clinically relevant P-loop & Activation loop mutants. DCC-2036 is highly efficacious in animal models of human T315I CML. DCC-2036 is being developed as an orally administered treatment for CML. See Deciphera's webpage.