Direct and selective small-molecule activation of proapoptotic BAX

Gavathiotis, Evripidis; Reyna, Denis E.; Bellairs, Joseph A.; Leshchiner, Elizaveta S.; Walensky, Loren D.

doi:10.1038/nchembio.995

Cited by 155 publications

(172 citation statements)

References 44 publications

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“…By in silico screening libraries of small molecules for displacing their SAHB from its ligand BAX, Gavathiotis and colleagues have recently identified a BAX activator molecule, BAM7, which interacts selectively with the BAX trigger site but not with the canonical BH3-binding groove of prosurvival BCL-2 proteins. This compound (a pirazolone core substituted with different groups) induces BAX activation and BAX-mediated apoptosis in BAK-deficient cells (66). These data provide proof-of-concept that "activator" BH3 mimetics can be designed.…”

Section: Bam7: a Direct Bax Activatormentioning

confidence: 76%

BH3 Mimetics: Status of the Field and New Developments

Billard

2013

Molecular Cancer Therapeutics

198

192

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Targeting apoptosis is an attractive approach in cancer therapy. The BH3-only proteins of the BCL-2 family (having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members). The "BH3 mimetic" concept has prompted the development of small molecules capable of mimicking BH3-only proteins and thus inducing apoptosis. The prototype BH3 mimetic ABT-737 selectively targets the three prosurvival proteins BCL-X L , BCL-2, and BCL-W (but not MCL-1 or A1) and its oral derivative ABT-263 has proved promising in clinical trials. Some putative BH3 mimetics are also tested clinically while others are still being characterized. This article recapitulates the various known BH3 mimetics and presents the recent developments in the field. The latter include (i) the identification of molecular determinants responsible for the specific interactions between BH3 motifs and the binding grooves of prosurvival proteins and (ii) the characterization of new compounds and particularly BH3 mimetics that antagonize either selectively MCL-1 or BCL-2 or a broad range of prosurvival proteins. These data are critical advances toward the discovery of novel anticancer agents. Mol Cancer Ther; 12(9); 1691-700. Ó2013 AACR.

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Section: Bam7: a Direct Bax Activatormentioning

confidence: 76%

BH3 Mimetics: Status of the Field and New Developments

Billard

2013

Molecular Cancer Therapeutics

198

192

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“…Indeed, the development of full-length forms of BCL-2 family members, such as BAK, is an essential step in advancing our structural and biochemical understanding of the protein interaction dynamics that dictate their proapoptotic function in the membrane environment. Further, our characterization of the differential trigger sites for BAK and BAX provides a blueprint for the development of selective pharmacologic agents, such as recently described for BAX (50), to directly activate the death program in diseases of pathologic cell survival.…”

Section: Discussionmentioning

confidence: 99%

Direct activation of full-length proapoptotic BAK

Leshchiner

Braun

Bird

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

144

151

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Proapoptotic B-cell lymphoma 2 (BCL-2) antagonist/killer (BAK) and BCL-2-associated X (BAX) form toxic mitochondrial pores in response to cellular stress. Whereas BAX resides predominantly in the cytosol, BAK is constitutively localized to the outer mitochondrial membrane. Select BCL-2 homology domain 3 (BH3) helices activate BAX directly by engaging an α1/α6 trigger site. The inability to express full-length BAK has hampered full dissection of its activation mechanism. Here, we report the production of full-length, monomeric BAK by mutagenesisbased solubilization of its C-terminal α-helical surface. Recombinant BAK autotranslocates to mitochondria but only releases cytochrome c upon BH3 triggering. A direct activation mechanism was explicitly demonstrated using a liposomal system that recapitulates BAKmediated release upon addition of BH3 ligands. Photoreactive BH3 helices mapped both triggering and autointeractions to the canonical BH3-binding pocket of BAK, whereas the same ligands crosslinked to the α1/α6 site of BAX. Thus, activation of both BAK and BAX is initiated by direct BH3-interaction but at distinct trigger sites. These structural and biochemical insights provide opportunities for developing proapoptotic agents that activate the death pathway through direct but differential engagement of BAK and BAX.apoptosis | BCL-2 family | SAHB | stapled peptide | photocrosslinking

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“…In fact, pan-antiapoptotic Bcl-2 family inhibitors such as obatoclax and navitoclax are being tested in clinical trials Bak as a Molecular Target of Vitamin K2-Induced Apoptosis (O'Brien et al, 2009;Gandhi et al, 2011). Moreover, small molecules that directly bind to and activate Bax in vitro have been developed and are expected to be used for cancer treatment (Gavathiotis et al, 2012). Thus members of the Bcl-2 family are promising targets for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis

et al. 2012

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Vitamin K2 (VK2, menaquinone) is known to have anticancer activity in vitro and in vivo. Although its effect is thought to be mediated, at least in part, by the induction of apoptosis, the underlying molecular mechanism remains elusive. Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis. VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis. Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death. Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak. Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction. Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis. This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.

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Direct and selective small-molecule activation of proapoptotic BAX

Cited by 155 publications

References 44 publications

BH3 Mimetics: Status of the Field and New Developments

BH3 Mimetics: Status of the Field and New Developments

Direct activation of full-length proapoptotic BAK

Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis

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