DCC-2036

Hersteller MedChem Express
Kategorie
Typ Inhibitors
Specific against other
Menge 10mg
ArtNr HY-13024-10mg
eClass 6.1 30220300
eClass 9.0 32160605
Lieferbar
Synonyms
Rebastinib, DCC 2036, DCC2036
CAS No.
1020172-07-9
Purity
>98%
MW
5535869
Formula
C30H28FN7O3
Solubility
10 mM in DMSO
Biological 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 PDGFRalpha, and PDGFRbeta 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 uM 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].
Publications
J Med Chem. 2015 Jan 8; 58(1):466-79.
Menge: 10mg
Lieferbar: In stock
Listenpreis: 225,71 €
Rabatt: -10,0%
Preis: 203,14 €
Sie sparen: 22,57 €
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