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DCC-2036 (Rebastinib)

Bcr-Abl inhibitor CAS# 1020172-07-9

DCC-2036 (Rebastinib)

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Chemical Properties of DCC-2036 (Rebastinib)

Cas No. 1020172-07-9 SDF Download SDF
PubChem ID 25066467 Appearance Powder
Formula C30H28FN7O3 M.Wt 553.59
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Rebastinib
Solubility DMSO : 50 mg/mL (90.32 mM; ultrasonic and warming and heat to 80°C)
Chemical Name 4-[4-[(5-tert-butyl-2-quinolin-6-ylpyrazol-3-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
SMILES CC(C)(C)C1=NN(C(=C1)NC(=O)NC2=C(C=C(C=C2)OC3=CC(=NC=C3)C(=O)NC)F)C4=CC5=C(C=C4)N=CC=C5
Standard InChIKey WVXNSAVVKYZVOE-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of DCC-2036 (Rebastinib)

DescriptionDCC-2036 (Rebastinib) is an inhibitor of Bcr-Abl with IC50 of 0.8 nM and 4 nM for Abl1(WT) and Abl1(T315I), respectively.
Targetsu-Abl1 (native)Abl1 (H396P)p-Abl1 (native)FLT3p-Abl1 (T315I)  
IC500.75 nM1.4 nM2 nM2 nM4 nM  

Protocol

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].

Cell Assay [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].

Animal Administration [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).

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.

DCC-2036 (Rebastinib) Dilution Calculator

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Preparing Stock Solutions of DCC-2036 (Rebastinib)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.8064 mL 9.032 mL 18.0639 mL 36.1278 mL 45.1598 mL
5 mM 0.3613 mL 1.8064 mL 3.6128 mL 7.2256 mL 9.032 mL
10 mM 0.1806 mL 0.9032 mL 1.8064 mL 3.6128 mL 4.516 mL
50 mM 0.0361 mL 0.1806 mL 0.3613 mL 0.7226 mL 0.9032 mL
100 mM 0.0181 mL 0.0903 mL 0.1806 mL 0.3613 mL 0.4516 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on DCC-2036 (Rebastinib)

DCC-2036 is a conformational control inhibitor of ABL1 with IC50 value of 0.8nM [1].

DCC-2036 is synthesized as a dual-anchoring inhibitor that binds both the switch control pocket E282/R386 pair and the Met318 ATP hinge. It shows a IC50 value of 0.8nM. DCC-2036 also exerts potent inhibition of the gatekeeper mutant ABL1T315I with IC50 value of 4nM. DCC-2036 inhibits ABL1 through forcing the kinase domains into inhibitor-bound, inactive Type II conformations. For the purified ABL1, DCC-2036 strongly inhibits unphosphorylated native ABL1, phosphorylated native ABL1, ABL1H396P, unphosphorylated ABL1T315I and phosphorylated ABL1T315I with IC50 values of 0.82nM, 2nM, 1.4nM, 5nM and 4nM, respectively. It is found that DCC-2036 inhibits ABL1 in a non-ATP-competitive manner. In cellular assay, DCC-2036 inhibits the proliferation of Ba/F3 and K562 cells with IC50 values of 5.4nM and 5.5nM, respectively. Moreover, treatment of DCC-2036 can effectively prolong survival in mice bearing Ba/F3-BCR-ABL1T315I leukemia cells. DCC-2036 is also capable to inhibit BCR-ABL1 in primary leukemic cells from patients with Ph+ leukemia [1].

References:
[1] Chan W W, Wise S C, Kaufman M D, 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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References on DCC-2036 (Rebastinib)

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.[Pubmed:27927766]

Haematologica. 2017 Mar;102(3):519-528.

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).

Description

Rebastinib (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.

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