ABT-263 (Navitoclax)

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S1001

5~200mg

Brand

Selleckchem

Description

ABT-263 (Navitoclax)

Catalog No.S1001

12 Reviews 20 Product Citations

ABT-263 (Navitoclax) is a potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with K_i of ≤ 0.5 nM, ≤1 nM and ≤1 nM, but binds more weakly to Mcl-1 and A1. Phase 1/2.

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Biological Activity

Description	ABT-263 (Navitoclax) is a potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with K_i of ≤ 0.5 nM, ≤1 nM and ≤1 nM, but binds more weakly to Mcl-1 and A1. Phase 1/2.
Targets	Bcl-xL	Bcl-2	Bcl-w
IC50	≤ 0.5 nM (K_i)	≤1 nM (K_i)	≤ 1 nM (K_i)^[1]
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 μM. 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]
Features

Protocol(Only for Reference)

Kinase Assay:

^[1]

Affinity determination	Binding affinities (K_i 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.

Affinity determination

Binding affinities (K_i 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.

Cell Assay:

^[1]

Cell lines	SCLC cell lines
Concentrations	0-1 μM
Incubation Time	48 hours
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 (1-5×10 ⁴) are treated by ABT-263 for 48 hours in 96-well culture plates in a final volume of 100 μL and cytotoxicity is assessed with the CellTiter Glo assay. In vitro cyto toxicity of ABT-263 is assayed.

Animal Study:

^[1]

Animal Models	C.B.-17 scid-bg or C.B.-17 scid mice
Dosages	100 mg/kd/d
Administration	Administered via p.o.

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01121133	Completed	Lymphoma, Including Chronic Lymphocytic Leukemia\|Solid Tumors	Abbott	2010-05	Phase 1
NCT01087151	Completed	Chronic Lymphocytic Leukemia	Genentech\|AbbVie (prior sponsor, Abbott)	2010-08	Phase 2
NCT01423539	Withdrawn	Lymphoma, B-Cell	Genentech\|AbbVie (prior sponsor, Abbott)	2011-10	Phase 2
NCT01557777	Active, not recruiting	Chronic Lymphocytic Leukemia	AbbVie\|AbbVie (prior sponsor, Abbott)	2012-06	Phase 2
NCT01828476	Not yet recruiting	Castrate Refractory Prostate Cancer (CRPC)	University of Medicine and Dentistry New Jersey\|AbbVie	2013-04	Phase 2

Chemical Information

Download ABT-263 (Navitoclax) SDF

Molecular Weight (MW)	974.61
Formula	C₄₇H₅₅ClF₃N₅O₆S₃
CAS No.	923564-51-6

Storage	3 years -20â„ƒPowder
Storage	6 months-80â„ƒin DMSO
Syonnyms	N/A

Solubility (25°C) *	In vitro	DMSO	100 mg/mL (102 mM)
		Water	<1 mg/mL (<1 mM)
		Ethanol	<1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Name

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.97461	9.7461	19.4922	29.2383

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Customer Reviews (12)

Click to enlarge	Rating
	Source	Biochem Biophys Res Commun, 2011, 408(2), 344-9. ABT-263 (Navitoclax) purchased from Selleck
	Method	Flow cytometry
	Cell Lines	MDCKII wild type cells/MDR1 cells
	Concentrations	50 nM
	Incubation Time	24 h
	Results	MDCKII cells transfected with MDR1 showed significantly less apoptosis inducedby ABT-737 (Fig. C) and ABT-263 (Fig. D) than wild type cells.