Small molecule SJ572946 activates BAK to initiate apoptosis

Sekar, Giridhar; Singh, Geetika; Qin, Xingping; Guibao, Cristina D.; Schwam, Brittany; Inde, Zintis; Grace, Christy R.; Zhang, Weixing; Slavish, P.J.; Lin, Wenwei; Chen, Taosheng; Lee, Richard; Rankovic, Zoran; Sarosiek, Kristopher A.; Moldoveanu, Tudor

doi:10.1016/j.isci.2022.105064

Cited by 7 publications

(8 citation statements)

References 66 publications

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“…[104] In AKO cells R127A BAK is so severely defective, with signs of misfolding and degradation, that only the combination of SJ572946 + BID could activate it. [104] Importantly, all activation impaired BAK mutants can be expressed stably in AKO cells whereas WT BAK could not be expressed, [96,104] as documented in a recent study also for WT BAX. [67] However, we identified a BAK mutant, V74A, that behaves like the wildtype BAK for all intents and purposes, and which can be stably expressed in AKO cells providing an unprecedented opportunity to investigate cellular BAK alone in the absence of the BCL-2 family repertoire.…”

Section: Bak and Bax Are Directly Activated By Bh3-only Initiators Au...mentioning

confidence: 99%

“…This mutant was used to investigate autoactivation and direct activation by tBID and small molecules. [96,104] To our knowledge a similar mutant has not been characterized for BAX yet.…”

Section: Bak and Bax Are Directly Activated By Bh3-only Initiators Au...mentioning

confidence: 99%

“…Remarkably, even a BAK mutant (R127A), which does not bind the prototypical BID BH3 ligand, could be activated in vitro by a recently described novel small molecule BAK activator, SJ572946. [104] In AKO cells R127A BAK is so severely defective, with signs of misfolding and degradation, that only the combination of SJ572946 + BID could activate it. [104] Importantly, all activation impaired BAK mutants can be expressed stably in AKO cells whereas WT BAK could not be expressed, [96,104] as documented in a recent study also for WT BAX.…”

Section: Bak and Bax Are Directly Activated By Bh3-only Initiators Au...mentioning

confidence: 99%

“…[103] Combined the mutagenesis and structural studies provide compelling evidence supporting the mechanisms of BAK and BAX activation through combination of direct activation, autoactivation in trans, and crossactivation (Figure 4A). [96,103,104] Mechanisms of BAK and BAX activation beyond the BH3-only initiators…”

Section: Bak and Bax Are Directly Activated By Bh3-only Initiators Au...mentioning

confidence: 99%

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Apoptotic mitochondrial poration by a growing list of pore‐forming BCL‐2 family proteins

Moldoveanu

2023

BioEssays

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The pore‐forming BCL‐2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK and BAX undergo direct activation by BH3‐only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super‐resolution microscopy images. The BH3‐in‐groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector‐mediated mitochondrial poration.

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Section: Bak and Bax Are Directly Activated By Bh3-only Initiators Au...mentioning

confidence: 99%

“…This mutant was used to investigate autoactivation and direct activation by tBID and small molecules. [96,104] To our knowledge a similar mutant has not been characterized for BAX yet.…”

Section: Bak and Bax Are Directly Activated By Bh3-only Initiators Au...mentioning

confidence: 99%

Section: Bak and Bax Are Directly Activated By Bh3-only Initiators Au...mentioning

confidence: 99%

Section: Bak and Bax Are Directly Activated By Bh3-only Initiators Au...mentioning

confidence: 99%

See 2 more Smart Citations

Apoptotic mitochondrial poration by a growing list of pore‐forming BCL‐2 family proteins

Moldoveanu

2023

BioEssays

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“…17 Moreover, Niu et al discovered a small molecule capable to inhibit both pro-apoptotic Bak and Bax, 23 and in a recent study the authors identified a small molecule SJ572946 that mimics the role of the BH3 peptides and directly activates Bak selectively over Bax. 24 Furthermore, Park et al identified BKA-073, a small compound capable of activating Bak with a potent antitumor activity against lung cancer. 25 Despite the number of structure−activity relationships studies and the small molecules identified on Bak, a detailed study on the already known, as well as novel prospective allosteric sites of the whole protein have not yet been reported.…”

Section: ■ Introductionmentioning

confidence: 99%

A Step Forward toward Selective Activation/Inhibition of Bak, a Pro-Apoptotic Member of the Bcl-2 Protein Family: Discovery of New Prospective Allosteric Sites Using Molecular Dynamics

Vila-Julià

Pérez

Rubio-Martínez

2023

J. Chem. Inf. Model.

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Bak is a pro-apoptotic protein and a member of the Bcl-2 family that plays a key role in apoptosis, a programmed cell death mechanism of multicellular organisms. Its activation under death stimuli triggers the permeabilization of the mitochondrial outer membrane that represents a point of no return in the apoptotic pathway. This process is deregulated in many tumors where Bak is inactivated, whereas in other cases like in neurodegeneration, it exhibits an excessive response leading to disorders such as the Alzheimer disease. Members of the Bcl-2 family share a common 3D structure, exhibiting an extremely similar orthosteric binding site, a place where both pro and antiapoptotic proteins bind. This similarity raises a selectivity issue that hampers the identification of new drugs, capable of altering Bak activation in a selective manner. An alternative activation site triggered by antibodies has been recently identified, opening the opportunity to undertake new drug discovery studies. Despite this recent identification, an exhaustive study to identify cryptic pockets as prospective allosteric sites has not been yet performed. Thus, the present study aims to characterize novel hotspots in the Bak structure. For this purpose, we have carried out extensive molecular dynamics simulations using three different Bak systems including Bak in its apo form, Bak in complex with its endogen activator Bim and an intermediate form, set up by removing Bim from the previous complex. The results reported in the present work shed some light on future docking studies on Bak through the identification of new prospective allosteric sites, not previously described in this protein.

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Mitochondrial pores at the crossroad between cell death and inflammatory signaling

2023

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Small molecule SJ572946 activates BAK to initiate apoptosis

Cited by 7 publications

References 66 publications

Apoptotic mitochondrial poration by a growing list of pore‐forming BCL‐2 family proteins

Apoptotic mitochondrial poration by a growing list of pore‐forming BCL‐2 family proteins

A Step Forward toward Selective Activation/Inhibition of Bak, a Pro-Apoptotic Member of the Bcl-2 Protein Family: Discovery of New Prospective Allosteric Sites Using Molecular Dynamics

Mitochondrial pores at the crossroad between cell death and inflammatory signaling

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