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Bafetinib

Catalog No. S1369 Name Selleck Chemicals
CAS Number 859212-16-1 Website http://www.selleckchem.com
M. F. C30H31F3N8O Telephone (877) 796-6397
M. W. 576.6153496 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 72642

SYNONYMS

IUPAC name
4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-N-(4-methyl-3-{[5-(pyrimidin-5-yl)pyrimidin-2-yl]amino}phenyl)-3-(trifluoromethyl)benzamide
IUPAC Traditional name
4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-N-(4-methyl-3-{[5-(pyrimidin-5-yl)pyrimidin-2-yl]amino}phenyl)-3-(trifluoromethyl)benzamide
Synonyms
NS-187
INNO-406

DATABASE IDS

CAS Number 859212-16-1

PROPERTIES

Target Bcr-Abl
Salt Data Free Base
Storage Condition -20°C

DETAILS

Description (English)
Research Area
Description Chronic myeloid leukaemia
Biological Activity
Description Bafetinib (INNO-406) is a potent and selective dual Bcr-Abl/Lyn inhibitor with IC50 of 5.8 nM and 19 nM, respectively.
Targets Abl Lyn
IC50 5.8 nM 19 nM [1]
In Vitro Bafetinib blocks WT Bcr-Abl autophosphorylation and its downstream kinase activity with IC50 of 11 nM and 22 nM in K562 and 293T cells, respectively. Bafetinib suppresses the growth of the Bcr-Abl-positive cell lines including K562, KU812, and BaF3/wt cells potently without effects on the proliferation of the Bcr-Abl-negative U937 cell line. Moreover, Bafetinib exhibits a dose-dependent antiproliferative effect against Bcr-Abl point mutant cell lines, such as BaF3/E255K cells. [1] In Bcr-Abl+ leukemia cell lines, Bafetinib induces both caspase-mediated and caspase-independent cell death by blocking the phosphorylation of Bcr-Abl. [2]
In Vivo In Bcr-Abl–positive KU812 mouse model, Bafetinib (0.2 mg/kg/day) significantly inhibits tumor growth, and completely inhibits tumor growth without adverse effects at 20 mg/kg/day. For Balb/c mice, Bafetinib shows maximal tolerated dose of 200 mg/kg/d and bioavailability value (BA) of 32%. [1] In a Central nervous system (CNS) leukemia model bearing Ba/F3/wt bcr-ablGFP, Ba/F3/Q252H, or Ba/F3/M351T cells, combination treatment of Bafetinib (60 mg/kg) and cyclosporine A (CsA) (50 mg/kg) leads to more significant inhibition of leukemia growth in the brain than either Bafetinib or CsA alone. [3]
Clinical Trials Bafetinib is currently in Phase II clinical trials in patients with hormone refractory prostate cancer.
Features Dual Bcr-Abl/Lyn inhibitor
Protocol
Kinase Assay [1]
Kinase assay Bcr-Abl kinase assays are performed in 25 μL of reaction mixture containing 250 μM peptide substrate, 740 Bq/μL [γ-33P]ATP, and 20 μM cold adenosine triphosphate (ATP) by using the SignaTECT protein tyrosine kinase assay system. Each Bcr-Abl kinase is used at a concentration of 10 nM. Kinase assays for Abl, Src, and Lyn are carried out with an enzyme-linked immunosorbent assay (ELISA) kit. The inhibitory effects of NS-187 against 79 tyrosine kinases are tested with KinaseProfiler.
Cell Assay [1]
Cell Lines K562, BaF3/wt, BaF3/E255K, and BaF3/T315I cells
Concentrations 0-10 μM
Incubation Time 72 hours
Methods K562, BaF3/wt, BaF3/E255K, and BaF3/T315I cells are plated at 1 × 103 in 96-well plates, whereas KU812 and U937 cells are plated at 5 × 103 in 96-well plates. Cells are incubated with serial dilutions of Bafetinib for 3 days. Cell proliferation is measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Nacalai Tesque) assay, and the 50% inhibitory concentration (IC50) values are calculated by fitting the data to a logistic curve.
Animal Study [1]
Animal Models KU812 xenograft is established by subcutaneous injection of KU812 cells into the right flank of Balb/c-nu/nu female mice.
Formulation Bafetinib is dissolved in 0.5% methylcellulose.
Doses ≤20 mg/kg/day
Administration Administered via p.o.
References
[1] Kimura S, et al. Blood. 2005, 106(12), 3948-3954.
[2] Kamitsuji Y, et al. Cell Death Differ. 2008, 15(11), 1712-2172.
[3] Yokota A, et al. Blood. 2007, 109(1), 306-314.