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Navitoclax

Overexpression of the prosurvival Bcl-2 family members (eg, Bcl-2, Bcl-XL) is associated with tumor progression.1

ABT263
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The Bcl-2 family members inhibit the intrinsic apoptotic pathway by sequestering and neutralizing pro-apoptotic proteins.1 Navitoclax is a small-molecule inhibitor being developed in collaboration with Abbott. This inhibitor targets anti-apoptotic Bcl-2 family proteins such as Bcl-2 and Bcl-XL, and thus may cause cells to undergo programmed cell death.1

  1. Apoptosis is often evaded in cancer cells via overexpression of anti-apoptotic Bcl-2 family proteins (eg, Bcl-2, Bcl-XL) and dysregulation of pro-apoptotic proteins.2,3 The Bcl-2 family members bind pro-apoptotic proteins to prevent apoptosis mediated by the intrinsic apoptotic pathway.2,4,5

    Navitoclax Vignette 1
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  2. Navitoclax is a potent inhibitor of anti-apoptotic Bcl-2 family proteins in preclinical models.1,6,7 It binds to these proteins and restores the ability of the intrinsic apoptotic pathway to respond to apoptotic stimuli.1,6,7

    Navitoclax Vignette 2
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Preclinical studies suggest that Navitoclax may cause cells to undergo programmed cell death.8

References:
1.
Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421-3428.
2.
Jin Z., El-Deiry, WS. Overview of cell death signaling pathways. Cancer Biol Ther. 2005;4:139-163.
3.
Lessene G, Cazbolar PE, Coleman PM BLC-2 family antagonists for cancer therapy. Nat Rev Drug Disc. 2008;7:989-1000
4.
Häcker G, Weber A. BH3-only proteins trigger cytochrome c release, but how? Arch Biochem Biophys. 2007;462:150-155.
5.
Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324-1337.
6.
Shoemaker AR, Mitten MJ, Oleksijew A, et al. The Bcl-2 family inhibitor ABT-263 shows significant anti-tumor efficacy in models of B cell non-Hodgkin's lymphoma. Blood. 2006;108:A825.
7.
Fesik SW. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer. 2005;5:876-885.