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Targeting BCL-2 Family Proteins:
Inhibiting the inhibitors of apoptosis

Bcl-2

Bcl-2

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

Bcl-2 family members inhibit the intrinsic apoptotic pathway by sequestering and neutralizing pro-apoptotic proteins.2 Navitoclax and GDC-0199 are 2 small-molecule inhibitors being developed in collaboration with Abbott Laboratories. These inhibitors are designed to target the anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-XL, which may cause cells to undergo programmed cell death.1-3

  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.4,5 The Bcl-2 family members bind pro-apoptotic proteins to prevent apoptosis mediated by the intrinsic apoptotic pathway.4,6,7

    Navitoclax Vignette 1
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  2. Navitoclax is designed to inhibit anti-apoptotic Bcl-2 and Bcl-XL. It binds to these proteins and may restore the ability of the intrinsic apoptotic pathway to respond to apoptotic stimuli.1,3 . Preclinical studies suggest that Navitoclax may cause cells to undergo programmed cell death.8

    Navitoclax Vignette 2
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  3. GDC-0199 is a small-molecule inhibitor designed to bind and inhibit the function of Bcl-2 specifically, which may restore the ability of the intrinsic apoptotic pathway to respond to apoptotic stimuli.2

Bcl-2 Vignette 1
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References:
1.
Reed JC. Bcl-2 family proteins and hematologic malignancies: history and future prospects. Blood. 2008;111:3322-3330.
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.
Garber K. New apoptosis drugs face critical test. Nat Biotechnol. 2005;23:409-411.
5.
Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324-1337.
6.
Häcker G, Weber A. BH3-only proteins trigger cytochrome c release, but how? Arch Biochem Biophys. 2007;462:150-155.
7.
Reed JC. Proapoptotic multidomain Bcl2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ. 2006;13:1378-1386.
8.
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.