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ABT-263

Names

[ CAS No. ]:
923564-51-6

[ Name ]:
ABT-263

[Synonym ]:
4-(4-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide
Navitoclax
Benzamide, 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]-
ABT263
4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide
(R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
4-[4-[[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide
ABT-263

Biological Activity

[Description]:

Navitoclax (ABT-263) is a potent and oral Bcl-2 family protein inhibitor that binds to multiple anti-apoptotic Bcl-2 family proteins, such as Bcl-xL, Bcl-2 and Bcl-w, with a Ki of less than 1 nM.

[Related Catalog]:

Signaling Pathways >> Apoptosis >> Bcl-2 Family
Research Areas >> Cancer

[Target]

Bcl-W:1 nM (Ki)

Bcl-xL:1 nM (Ki)

Bcl-2:1 nM (Ki)


[In Vitro]

Navitoclax (ABT-263) is active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC50 for all of the lines in the panel is 1.91 µM[1]. Navitoclax in combination with chemotherapy agents leads most ovarian cancer cell lines a synergistic response, and enhances the caspase activation at all paclitaxel doses tested in both SK-OV-3 and IGROV-1 cell lines[2].

[In Vivo]

Navitoclax (100 mg/kg/day, p.o.) also improves responses to bendamustine-rituximab (BR) in a subset of tumours in mice xenograft[3].

[Kinase Assay]

To measure caspase-3/7 activation, IGROV-1 and SKOV3 cells are seeded in 96-well plates at 5,000 cells per well. After 24 hours, cells are treated with navitoclax (1 μM), paclitaxel (dose range=1-100 nM), or in combination with navitoclax and paclitaxel using the same dosing concentrations. Each treatment is done in duplicate wells. Induction of apoptosis, following treatment at time 0, 4, 24, and 48 hours, is determined using a Caspase-Glo 3/7 assay. A DMSO control is included in all studies. The experiment is conducted twice, and the data are presented as an average of both runs.

[Cell Assay]

Cells are seeded in 384-well plates at 3,000 cells per well. After 24 hours, cells are treated with navitoclax (dose range of 14 nM-3.3 μM) and paclitaxel (dose range of 15 pM-100 nM) or gemcitabine (dose range of 0.5 nM-3.3 μM) in a 9 by 7 matrix. Each treatment is carried out in quadruplicate. Cells are treated for 72 hours, and cell viability is determined using the CellTiter-Glo assay. Cell viability for each treatment is normalized against the DMSO control group.

[Animal admin]

For systemic Granta 519 tumour models, 2×106 cells are injected via the tail vein in 0.1 mL volume of cell medium on day 0, and treatment is initiated on day 14. All animals are ear-tagged and monitored individually throughout the experiment. Navitoclax is administered by oral gavage once daily in a mixture of Phosal 50PG : PEG400 : ethanol. Bendamustine and rituximab are administered i.v. at 25 and 10 mg/kg, respectively, on day 1. Navitoclax is administered approximately 2 h before bendamustine and rituximab. All trials are comprised of 10 mice per group. Mice are humanely killed when tumours reached a size >2000 mm3 or when any signs of distress are monitored. Signs of distress include loss of ambulation, laboured breathing or weight loss > 20% mean body weight per cage.

[References]

[1]. Lock R1, et al. Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Jun;50(6):1181-1189.

[2]. Wong M, et al. Navitoclax (ABT-263) reduces Bcl-x(L)-mediated chemoresistance in ovarian cancer models.Mol Cancer Ther. 2012 Apr;11(4):1026-1035.

[3]. Ackler S, et al. Navitoclax (ABT 263) and Bendamustine±Rituximab Induce Enhanced Killing of Non-Hodgkin's Lymphoma Tumors in Vivo. Br J Pharmacol. 2012 Oct;167(4):881-891.


[Related Small Molecules]

Venetoclax (ABT-199) | S63845 | ABT-737 | Obatoclax Mesylate | A-1210477 | A-1155463 | WEHI-539 hydrochloride | A-1331852 | Bax inhibitor peptide V5 | FX 1 | Gambogic Acid | TW-37 | UMI-77 | Acetate gossypol | HA14-1

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Melting Point ]:
114-116ºC

[ Molecular Formula ]:
C47H55ClF3N5O6S3

[ Molecular Weight ]:
974.613

[ Exact Mass ]:
973.295532

[ PSA ]:
170.42000

[ LogP ]:
12.14

[ Index of Refraction ]:
1.655

[ Storage condition ]:
-20°C Freezer, Under Inert Atmosphere

Safety Information

[ HS Code ]:
29339900

Related Compounds