ArticleCell death & disease2020
A small-molecule ARTS mimetic promotes apoptosis through degradation of both XIAP and Bcl-2.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Discovery of novel and highly potent XIAP-targeted peptide inhibitors using virtual screening.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- ARTS Confers Chemoresistance of Breast Cancer by Inducing Apoptosis-Dependent Autophagy via Livin-MDM2-p53 Pathway.Research (Washington, D.C.) · 2026Article
- Review
- Bioinformatics analysis reveals CTSF suppresses tumor cell malignant phenotype and CD8 + T cell exhaustion by downregulating Bcl- 2 protein in the microenvironment of bladder cancer.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Septin4 Regulates Cardiac Fibrosis After Pressure Overload.Circulation research · 2025Article
- TRIM22 promotes glioblastoma development by ubiquitinating Bcl-2.Molecular & cellular oncology · 2025Article
- The correlation between Smac, IAPs and mitochondrial apoptosis, muscle tenderness during postmortem aging of Oula Tibetan sheep meat.Food chemistry: X · 2024Article
- ARTS and small-molecule ARTS mimetics upregulate p53 levels by promoting the degradation of XIAP.Apoptosis : an international journal on programmed cell death · 2024Article
- Targeted Degradation of XIAP is Sufficient and Specific to Induce Apoptosis in MYCN-overexpressing High-risk Neuroblastoma.Cancer research communications · 2023Article
- The ARTS of p53-dependent mitochondrial apoptosis.Journal of molecular cell biology · 2023Review
- X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL.EMBO molecular medicine · 2023Article
- Apoptosis and tissue thinning contribute to symmetric cell division in the developing mouse epidermis in a nonautonomous way.PLoS biology · 2022Article
- SBP-0636457, a Novel Smac Mimetic, Cooperates with Doxorubicin to Induce Necroptosis in Breast Cancer Cells during Apoptosis Blockage.Journal of oncology · 2022Article
- Review
- Septin4 promotes cardiomyocytes apoptosis by enhancing the VHL-mediated degradation of HIF-1α.Cell death discovery · 2021Article
- Review
- Septins promote caspase activity and coordinate mitochondrial apoptosis.Cytoskeleton (Hoboken, N.J.)Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Many human cancers over-express B cell lymphoma 2 (Bcl-2) or X-linked inhibitor of apoptosis (IAP) proteins to evade cell death. The pro-apoptotic ARTS (Sept4_i2) protein binds directly to both Bcl-2 and XIAP and promotes apoptosis by stimulating their degradation via the ubiquitin-proteasome system (UPS). Here we describe a small molecule, A4, that mimics the function of ARTS. Microscale thermophoresis assays showed that A4 binds XIAP, but not cellular inhibitor of apoptosis protein 1 (cIAP1). A4 binds to a distinct ARTS binding pocket in the XIAP-BIR3 (baculoviral IAP repeat 3) domain. Like ARTS, A4 stimulated poly-ubiquitylation and UPS-mediated degradation of XIAP and Bcl-2, but not cIAP1, resulting in caspase-9 and -3 activation and apoptosis. In addition, over-expression of XIAP rescued HeLa cells from A4-induced apoptosis, consistent with the idea that A4 kills by antagonizing XIAP. On the other hand, treatment with the SMAC-mimetic Birinapant induced secretion of tumour necrosis factor-α (TNFα) and killed ~50% of SKOV-3 cells, and addition of A4 to Birinapant-treated cells significantly reduced secretion of TNFα and blocked Birinapant-induced apoptosis. This suggests that A4 acts by specifically targeting XIAP. The effect of A4 was selective as peripheral blood mononuclear cells and normal human breast epithelial cells were unaffected. Furthermore, proteome analysis revealed that cancer cell lines with high levels of XIAP were particularly sensitive to the killing effect of A4. These results provide proof of concept that the ARTS binding site in XIAP is "druggable". A4 represents a novel class of dual-targeting compounds stimulating apoptosis by UPS-mediated degradation of important anti-apoptotic oncogenes.
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