Future Therapeutic Directions for Smac-Mimetics

Morrish, Emma; Brumatti, Gabriela; Silke, John

doi:10.3390/cells9020406

Cited by 102 publications

(121 citation statements)

References 164 publications

(221 reference statements)

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“…However, it remains an important goal to extend the utility of these agents to other types of cancer 71,72 . XIAP is another promising drug target for cancer therapy 38,45,46,73 . Silencing of XIAP was found to sensitize cells to chemotherapy and TRAIL receptor agonists and reduce resistance to chemotherapy 45 .…”

Section: Discussionmentioning

confidence: 99%

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A small-molecule ARTS mimetic promotes apoptosis through degradation of both XIAP and Bcl-2

Mamriev

Abbas

Klingler³

et al. 2020

Cell Death Dis

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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 A4induced 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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Section: Discussionmentioning

confidence: 99%

“…The vast majority of compounds that are currently developed as IAP antagonists (mainly SMs) act by binding and inhibiting XIAP rather than degrading it 38,73 . Similarly, BH3 mimetics, such as Venetoclax, act by binding and inhibiting Bcl-2 20,72 .…”

Section: Discussionmentioning

confidence: 99%

A small-molecule ARTS mimetic promotes apoptosis through degradation of both XIAP and Bcl-2

Mamriev

Abbas

Klingler³

et al. 2020

Cell Death Dis

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“…IAP are considered promising targets for the development of new anticancer compounds. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP‐binding motif of second mitochondria‐derived activator of caspase (Smac), which functions as an endogenous IAP antagonist [87] . Endogenous Smac homodimerizes through an extensive hydrophobic interface and is bivalent.…”

Section: Induction Of Cscs Differentiationmentioning

confidence: 99%

Differentiation of Cancer Stem Cells by Using Synthetic Small Molecules: Toward New Therapeutic Strategies against Therapy Resistance

et al. 2020

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Despite the existing arsenal of anti‐cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem‐like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC‐specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer‐differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.

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“…Natural IAP antagonists, such as the second mitochondria-derived activator of caspases (Smac/DIABLO), can sensitize cancers to cell death. This has led to the pharmaceutical development of small molecule peptide-mimetic IAP antagonists (Smac-mimetics) [5]. The Smac-mimetic birinapant has predominantly been investigated for the treatment of cancer [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Combinatorial Treatment of Birinapant and Zosuquidar Enhances Effective Control of HBV Replication In Vivo

Morrish

Mackiewicz

Silke

et al. 2020

Viruses

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Chronic hepatitis B virus (HBV) infection remains a global health threat and affects hundreds of millions worldwide. Small molecule compounds that mimic natural antagonists of inhibitor of apoptosis (IAP) proteins, known as Smac-mimetics (second mitochondria-derived activator of caspases-mimetics), can promote the death of HBV-replicating liver cells and promote clearance of infection in preclinical models of HBV infection. The Smac-mimetic birinapant is a substrate of the multidrug resistance protein 1 (MDR1) efflux pump, and therefore inhibitors of MDR1 increase intracellular concentration of birinapant in MDR1 expressing cells. Liver cells are known to express MDR1 and other drug pump proteins. In this study, we investigated whether combining the clinical drugs, birinapant and the MDR1 inhibitor zosuquidar, increases the efficacy of birinapant in killing HBV expressing liver cells. We showed that this combination treatment is well tolerated and, compared to birinapant single agent, was more efficient at inducing death of HBV-positive liver cells and improving HBV-DNA and HBV surface antigen (HBsAg) control kinetics in an immunocompetent mouse model of HBV infection. Thus, this study identifies a novel and safe combinatorial treatment strategy to potentiate substantial reduction of HBV replication using an IAP antagonist.

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Future Therapeutic Directions for Smac-Mimetics

Cited by 102 publications

References 164 publications

A small-molecule ARTS mimetic promotes apoptosis through degradation of both XIAP and Bcl-2

A small-molecule ARTS mimetic promotes apoptosis through degradation of both XIAP and Bcl-2

Differentiation of Cancer Stem Cells by Using Synthetic Small Molecules: Toward New Therapeutic Strategies against Therapy Resistance

Combinatorial Treatment of Birinapant and Zosuquidar Enhances Effective Control of HBV Replication In Vivo

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