Navitoclax Inhibitor CAS No. 923564-51-6

Cat. No.	Name	Size	Price
KI0226	Navitoclax	5 mg	$192
	Navitoclax	10 mg	$320
	Navitoclax	25 mg	$592
	Navitoclax	100 mg	$1552

Chemical Characteristic

Product Name	Navitoclax
Synonyms	ABT-263
CAS No.	923564-51-6
Molecular Weight	974.61
Formula	C₄₇H₅₅ClF₃N₅O₆S₃
Chemical Name	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
Smiles	C(=O)(c1ccc(cc1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)c1ccc(cc1)Cl)NS(=O)(=O)c1cc(c(cc1)NC(CCN1CCOCC1)CSc1ccccc1)S(=O)(=O)C(F)(F)F
Chemical Structure

Biological activities

Navitoclax is a potent and highly selective inhibitor of anti-apoptotic members of the Bcl-2 family, with binding affinities (K_{i??) <1 nM for Bcl-2, Bcl-xL, and Bcl-w, but K_{i of 550 nM for Mcl-1. Navitoclax induces Bax translocation, cytochrome c release, and subsequent apoptosis. ^[1] Meanwhile, navitoclax potentiates apoptosis triggered by paclitaxel and an inhibitor of kinesin-5 across a panel of epithelial cancer lines. Navitoclax has little effect on cell death during interphase, but strongly accelerates apoptosis during mitotic arrest, and greatly increases the fraction of apoptosis-resistant cells that die. In U2OS cells, navitoclax alone is cytotoxic, leading to approximately 35% cell death after 60 hours of drug treatment. Even in the most apoptosis-resistant A549 cells, navitoclax strongly enhances death during mitotic arrest for both antimitotics. ^[2] Navitoclax is slightly more potent than ABT-737 against FL5.12/Bcl-2 cells, with EC50 of 6.0 and 8.0 nM, respectively. Meanwhile, Navitoclax inhibits FL5.12/Bcl-xL cells with EC50 of 4.0 nM compared with ABT-737 of 30 nM. Navitoclax is also more metabolically stable, has better tissue distribution and has a lower overall charge at physiologically relevant pH ranges. ^[3] Navitoclax is a targeted high-affinity small molecule that occupies the BH3 binding groove of BCL-2 and BCL-X_{L and inhibits their anti-apoptotic activity. Navitoclax demonstrates broad activity against a panel of human tumor cell lines at an EC50 < 1 µM. In vivo, navitoclax induces durable and complete tumor regressions in a murine xenograft model of acute lymphocytic leukemia and significantly improves the cure rate of rituximab plus chemotherapy in a xenograft model of mantle cell lymphoma. ^[4] The combination of navitoclax and paclitaxel is synergistic in cell lines tested, with combined growth inhibition greater than 90%. Besides, addition of navitoclax to paclitaxel changes cell fate from mitotic slippage to death during mitotic arrest and causes an increase in cell death. ^[5]}}}

Protocols

Navitoclax is dissolved in DMSO at 10 mM and stored at -80°C. ^[1]

References

[1] Tse C, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008, 68(9): 3421-3428. [2] Shi J, et al. Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. Cancer Res.2011, 71(13): 4518-4526. [3] Wendt MD, et al. The discovery of navitoclax, a Bcl-2 family inhibitor. Topics in Medicinal Chemistry. 2012, 8: 231-258. [4] Wilson WH, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010, 11(12): 1149-1159. [5] Tan N, et al. Navitoclax enhances the efficacy of taxanes in non-small cell lung cancer models. Clin Cancer Res. 2011, 17(6): 1394-1404. [6] Shoemaker AR, et al. Activity of the Bcl-2 family inhibitor Navitoclax in a panel of small cell lung cancer xenograft models. Clin Cancer Res. 2008, 14(11): 3268-3277.

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