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Navitoclax (ABT-263)

Navitoclax (ABT-263)

Hersteller	Selleckchem
Kategorie	Oncology Food Safety Antibiotics Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Skin Cancer Colorectal Cancer Heart & Blood Cancer Testicular & Prostate Cancer Lymphatic System Cancer
Typ	Inhibitors
Specific against	other
Menge	10 mM/1 ml
ArtNr	S1001-10mM
CAS-Nr.	923564-51-6
eClass 6.1	30220300
eClass 9.0	32160605
Lieferbar
Administration	Administered via p.o.
Animal Models	C.B.-17 scid-bg or C.B.-17 scid mice
Cell lines	SCLC cell lines
Clinical Trials	ABT-263 is currently in Phase II clinical trial for the treatments of chronic lymphocytic leukemia.
Concentrations	0-1 uM
Description	ABT-263 (Navitoclax) is a potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with Ki of <= 0.5 nM, <=1 nM and <= 1 nM, respectively.
Dosages	100 mg/kd/d
Formulation	Formulated in 10% ethanol, 30% polyethylene glycol 400, and 60% Phosal 50 PG
IC50	<= 0.5 nM (Ki), <= 0.5 nM (Ki), <= 0.5 nM (Ki), <= 0.5 nM (Ki), <= 0.5 nM (Ki), <= 0.5 nM (Ki)
In vitro	ABT-263 is structurally related to ABT-737, it is a disruptor of Bcl-2/Bcl-xL interactions with pro-apoptotic proteins. Overexpression of the prosurvival Bcl-2 family members is commonly associated with tumor maintenance, progression, and chemoresistance. [1] ABT-263 displays the protection afforded by overexpression of Bcl-2 or Bcl-xL with EC50 values of 60 nM and 20 nM, respectively. [1] A wide range of cellular activity is observed with ABT-263 having a 50% growth inhibition (EC50) of 110 nM against the most sensitive line (H146), whereas its activity in the least sensitive line (H82) results in an EC50 at 22 uM. All four cell lines with EC50 values of <400 nM (H146, H889, H1963, and H1417) are also highly sensitive to ABT-737, and the two most resistant lines (H1048 and H82) are similarly resistant to ABT-263. [2]
In vivo	When ABT-263 is administered at 100 mg/kg/day in the H345 xenograft model, significant antitumor efficacy is observed with 80% TGI and 20% of treated tumors indicating at least a 50% reduction in tumor volume. [2] Oral administration of ABT-263 alone causes complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 displays modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. [2]
Incubation Time	48 hours
Kinase Assay	Affinity determination, Binding affinities (Ki or IC50) of ABT-263 against different isoforms of Bcl-2 family are determined with competitive fluorescence polarization assays. The following peptide probe/protein pairs are used: f-bad (1 nM) and Bcl-xL (6 nM), f-Bax (1 nM) and Bcl-2 (10 nM), f-Bax (1 nM) and Bcl-w (40 nM), f-Noxa (2 nM) and Mcl-1 (40 nM), and f-Bax (1 nM) and Bcl-2-A1 (15 nM). Binding affinities for Bcl-xL are also determined using a time-resolved fluorescence resonance energy transfer assay. Bcl-xL (1 nM, His tagged) is mixed with 200 nM f-Bak, 1 nM Tb-labeled anti-His antibody, and ABT-263 at room temperature for 30 min. Fluorescence is measured on an Envision plate reader using a 340/35 nm excitation filter and 520/525 (f-Bak) and 495/510 nm (Tb-labeled anti-His antibody) emission filters.
Method	Human tumor cell lines SCLC cell lines are maintained at 37 C containing 5% CO2. SCLC cell lines are cultured in RPMI 1640 with 10% fetal bovine serum (FBS), 1% sodium pyruvate, 25 mM HEPES, 4.5 g/L glucose, and 1% penicillin/streptomycin. Leukemia and lymphoma cell lines are cultured in RPMI 1640 supplemented with 10% FBS and 1% penicillin/streptomycin. Cells (1-510 4) are treated by ABT-263 for 48 hours in 96-well culture plates in a final volume of 100 L and cytotoxicity is assessed with the CellTiter Glo assay. In vitro cyto toxicity of ABT-263 is assayed.
Molecular Weight (MW)	974, 61
Picture ChemicalStructure Description	ABT-263 (Navitoclax) Chemical Structure
Picture Description 1	Data from [PLoS ONE , 2011, 6, e21980], ABT-263 (Navitoclax)purchased from Selleck, HCC cells are resistant to low doses of ABT-263. A. LH86 and B. Huh7 cells were treated with ABT-263 (0-20 M) for up to 24 h. Apoptosis was measured through Hoechst staining to show apoptotic cells with condensed nuclei as described in materials and methods.(representative apoptotic cells were marked with white arrows in ABT-263 treatment panel). C. HCC cells were treated with increasing doses of ABT-263 as indicated for up to 24 h. Then cells were harvested and cell lysates were prepared and subjected to Western blotting. Caspase activation was assessed through detecting the cleaved bands of caspase 9 and caspase 3. -actin protein levels were used as an equal protein loading control.
Picture Description 2	Data from [Clin Cancer Res , 2010, 16, 4217-4225], ABT-263 (Navitoclax)purchased from Selleck, The reduced biological activity of ABT-263 is not due to a reduced potency or plasma membrane permeability. A, F-dextran-loaded liposomes were incubated with BAX, N/C-BID, and BCL-XL, and the indicated concentrations of ABT-737 or ABT-263 (0.04, 0.2, 1, or 5 mol/L) for 2.5 hours at room temperature. Both ABT-737 and ABT-263 reversed BCL-XL-mediated inhibition of BAX and N/C-BID liposome permeabilization (n = 3). B, purified CLL cells were treated with 0.05% digitonin to permeabilize the plasma membrane and the cells were washed and pelleted by centrifugation at 13, 000 rpm. The permeabilized cells were incubated with different concentrations of ABT-737 and ABT-263 for 1 hour at 37C. The release of cytochrome c (Cyt c) from the cell pellet into the supernatant (SN) was assessed after centrifugation by Western blotting.
Solubility (25C)	DMSO 195 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Storage	2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO

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Menge: 10 mM/1 ml

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