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Bafetinib (INNO-406; NS187) 859212-16-1

Bafetinib (INNO-406; NS187) 859212-16-1

CAS No.: 859212-16-1

Bafetinib (formerly INNO406; NS-187), an investigational anticancer drug originally developed by Nippon Shinyaku and lat
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Bafetinib (formerly INNO406; NS-187), an investigational anticancer drug originally developed by Nippon Shinyaku and later licensed to CytRx, is an orally bioavailable dual Bcr-Abl/Lyn inhibitor with potential antineoplastic activity. It inhibits Bcr-Abl/Lyn with IC50s of 5.8 nM/19 nM in cell-free assays. In Bcr-Abl–positive KU812 mouse model, Bafetinib significantly inhibited tumor growth, and completely inhibited tumor growth without causing adverse effects at a dose of 20 mg/kg/day.


Physicochemical Properties


Molecular Formula C30H31F3N8O
Molecular Weight 576.62
Exact Mass 576.257
CAS # 859212-16-1
Related CAS # 859212-16-1;887650-05-7;
PubChem CID 11387605
Appearance Light yellow to yellow solid powder
Density 1.4±0.1 g/cm3
Melting Point 166-168°C
Index of Refraction 1.640
LogP 3.03
Hydrogen Bond Donor Count 2
Hydrogen Bond Acceptor Count 11
Rotatable Bond Count 8
Heavy Atom Count 42
Complexity 872
Defined Atom Stereocenter Count 1
SMILES

CC1=C(C=C(C=C1)NC(=O)C2=CC(=C(C=C2)CN3CC[C@@H](C3)N(C)C)C(F)(F)F)NC4=NC=CC(=N4)C5=CN=CN=C5

InChi Key ZGBAJMQHJDFTQJ-DEOSSOPVSA-N
InChi Code

InChI=1S/C30H31F3N8O/c1-19-4-7-23(13-27(19)39-29-36-10-8-26(38-29)22-14-34-18-35-15-22)37-28(42)20-5-6-21(25(12-20)30(31,32)33)16-41-11-9-24(17-41)40(2)3/h4-8,10,12-15,18,24H,9,11,16-17H2,1-3H3,(H,37,42)(H,36,38,39)/t24-/m0/s1
Chemical Name

(S)-N-(3-([4,5'-bipyrimidin]-2-ylamino)-4-methylphenyl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)benzamide
Synonyms

INNO-406; INNO 406; NS187; NS187; INNO406;NS-187; NS 187
HS Tariff Code 2934.99.9001
Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month
Shipping Condition Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity


ln Vitro

In vitro activity: 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. In Bcr-Abl+ leukemia cell lines, Bafetinib induces both caspase-mediated and caspase-independent cell death by blocking the phosphorylation of Bcr-Abl.

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: 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 × 103in 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.
ln 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%. 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.
Animal Protocol
Bafetinib is dissolved in 0.5% methylcellulose; ≤20 mg/kg/day; p.o.
KU812 xenograft is established by subcutaneous injection of KU812 cells into the right flank of Balb/c-nu/nu female mice.
References Blood.2005 Dec 1;106(12):3948-54;Blood.2007 Jan 1;109(1):306-14.
Additional Infomation Bafetinib is a biaryl.
Bafetinib has been used in trials studying the treatment of Adult Gliosarcoma, Adult Mixed Glioma, Adult Glioblastoma, Chronic Myeloid Leukemia, and Acute Lymphocytic Leukemia, among others.
Bafetinib is an orally active 2-phenylaminopyrimidine derivative with potential antineoplastic activity. INNO-406 specifically binds to and inhibits the Bcr/Abl fusion protein tyrosine kinase, an abnormal enzyme produced by Philadelphia chromosomal translocation associated with chronic myeloid leukemia (CML). Furthermore, this agent also inhibits the Src-family member Lyn tyrosine kinase, upregulated in imatinib-resistant CML cells and in a variety of solid cancer cell types. The inhibitory effect of INNO-406 on these specific tyrosine kinases decreases cellular proliferation and induces apoptosis. A high percentage of CML patients are refractory to imatinib, which sometimes results from point mutations occurring in the kinase domain of the Bcr/Abl fusion product. Due to its dual inhibitory activity, INNO-406 has been shown to overcome this particular drug resistance and to be a potent and effective agent in the treatment of imatinib-resistant CML.

Solubility Data


Solubility (In Vitro)
DMSO: 100 mg/mL (173.4 mM)
Water:<1 mg/mL
Ethanol:<1 mg/mL
Solubility (In Vivo) Solubility in Formulation 1: ≥ 2.5 mg/mL (4.34 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 25.0 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: ≥ 2.5 mg/mL (4.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.
Solubility in Formulation 3: 0.5% methylcellulose+0.2% Tween 80: 30 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.7342 mL 8.6712 mL 17.3424 mL
5 mM 0.3468 mL 1.7342 mL 3.4685 mL
10 mM 0.1734 mL 0.8671 mL 1.7342 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.

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Is for research use only, not for human use. We do not sell to patients.