Structure‐based design and molecular profiling of Smac‐mimetics selective for cellular <scp>IAP</scp>s

Corti, Alessandro; Milani, Mario; Lecis, Daniele; Seneci, Pierfausto; Rosa, Matteo de; Mastrangelo, Eloise; Cossu, Federica

doi:10.1111/febs.14616

Cited by 13 publications

(15 citation statements)

References 56 publications

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“…Therefore, XIAP and cIAPs have become attractive targets for cancer therapy [45,51,88,94]. Most of the efforts to target IAPs were focused on developing Smac (IBM) mimetics [64,65,[95][96][97][98][99]. Here we will review the progress in developing Smac-based IAP-antagonists, and the initial efforts to develop ARTS-based small-molecule mimetics.…”

Section: Targeting Xiap For Cancer Therapy; Developing Smac and Arts mentioning

confidence: 99%

“…Smac mimetic (SM) small molecules were initially designed to bind and inhibit XIAP [53,98,[103][104][105]. However, these compounds turned out to be primarily active against cIAPs (Figure 2A) [28,99,106,107]. There are two types of Smac mimetics, monovalent and bivalent.…”

Section: Targeting Xiap For Cancer Therapy; Developing Smac and Arts mentioning

confidence: 99%

“…This ripotosome complex contains FADD, Caspase 8, and RIPK1/3 inducing either apoptosis or necroptosis depending on RIPK3 levels [114,[123][124][125][126][127]. In particular, Smac mimetic compounds SM130 and SM114 are selective for degradation of cIAP1 with reduced binding affinity for XIAP [99]. Birinapant (TL32711) is a bivalent compound that displays preferential binding to cIAP1 relative to cIAP2 and XIAP, which is currently being tested in clinical trials [128][129][130][131].…”

Section: Targeting Xiap For Cancer Therapy; Developing Smac and Arts mentioning

confidence: 99%

“…The current small molecule IAP antagonists bind and degrade cIAPs while binding XIAP with lower affinity [99,[128][129][130][131]. A major unmet goal of the pharmaceutical industry is therefore, to develop potent and specific small molecules that selectively degrade XIAP [87,143].…”

Section: Targeting Xiap For Cancer Therapy; Developing Smac and Arts mentioning

confidence: 99%

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Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC

Abbas

Larisch

2020

Cells

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Inhibitors of apoptosis (IAPs) are a family of proteins that regulate cell death and inflammation. XIAP (X-linked IAP) is the only family member that suppresses apoptosis by directly binding to and inhibiting caspases. On the other hand, cIAPs suppress the activation of the extrinsic apoptotic pathway by preventing the formation of pro-apoptotic signaling complexes. IAPs are negatively regulated by IAP-antagonist proteins such as Smac/Diablo and ARTS. ARTS can promote apoptosis by binding and degrading XIAP via the ubiquitin proteasome-system (UPS). Smac can induce the degradation of cIAPs but not XIAP. Many types of cancer overexpress IAPs, thus enabling tumor cells to evade apoptosis. Therefore, IAPs, and in particular XIAP, have become attractive targets for cancer therapy. In this review, we describe the differences in the mechanisms of action between Smac and ARTS, and we summarize efforts to develop cancer therapies based on mimicking Smac and ARTS. Several Smac-mimetic small molecules are currently under evaluation in clinical trials. Initial efforts to develop ARTS-mimetics resulted in a novel class of compounds, which bind and degrade XIAP but not cIAPs. Smac-mimetics can target tumors with high levels of cIAPs, whereas ARTS-mimetics are expected to be effective for cancers with high levels of XIAP.

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Section: Targeting Xiap For Cancer Therapy; Developing Smac and Arts mentioning

confidence: 99%

Section: Targeting Xiap For Cancer Therapy; Developing Smac and Arts mentioning

confidence: 99%

Section: Targeting Xiap For Cancer Therapy; Developing Smac and Arts mentioning

confidence: 99%

Section: Targeting Xiap For Cancer Therapy; Developing Smac and Arts mentioning

confidence: 99%

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Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC

Abbas

Larisch

2020

Cells

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“…In addition, the negative charge on NBC is higher in cIAPs due to substitution E/Q319 and E/K311 in cIAPs/XIAP, respectively. The different features of the IBM cavity were exploited for the selection of SMs with different affinity for cIAP- and XIAP-BIR3, as reported in Corti et al [ 89 ] and in Ndubaku et al [ 90 ]. Such selective molecules can be used to study different effects in apoptosis modulations in several cell lines and develop cIAPs-targeted therapies with reduced side-effects (mainly due to XIAP inhibition).…”

Section: Structure and Function Of Birs: The Ibm Groovementioning

confidence: 99%

Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment

Cossu

Milani

Mastrangelo

et al. 2019

Computational and Structural Biotechnology Journal

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Inhibitor of apoptosis (IAP) proteins are characterized by the presence of the conserved baculoviral IAP repeat (BIR) domain that is involved in protein-protein interactions. IAPs were initially thought to be mainly responsible for caspase inhibition, acting as negative regulators of apoptosis, but later works have shown that IAPs also control a plethora of other different cellular pathways. As X-linked IAP (XIAP), and other IAP, levels are often deregulated in cancer cells and have been shown to correlate with patients' prognosis, several approaches have been pursued to inhibit their activity in order to restore apoptosis. Many small molecules have been designed to target the BIR domains, the vast majority being inspired by the N-terminal tetrapeptide of Second Mitochondria-derived Activator of Caspases/Direct IAp Binding with Low pI (Smac/Diablo), which is the natural XIAP antagonist. These compounds are therefore usually referred to as Smac mimetics (SMs). Despite the fact that SMs were intended to specifically target XIAP, it has been shown that they also interact with cellular IAP-1 (cIAP1) and cIAP2, promoting their proteasome-dependent degradation. SMs have been tested in combination with several cytotoxic compounds and are now considered promising immune modulators which can be exploited in cancer therapy, especially in combination with immune checkpoint inhibitors. In this review, we give an overview of the structural hot-spots of BIRs, focusing on their fold and on the peculiar structural patches which characterize the diverse BIRs. These structures are exploited/exploitable for the development of specific and active IAP inhibitors.

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ARTS and small-molecule ARTS mimetics upregulate p53 levels by promoting the degradation of XIAP

Abbas,

Hartmann,

Asiss

et al. 2024

Apoptosis

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Mutations resulting in decreased activity of p53 tumor suppressor protein promote tumorigenesis. P53 protein levels are tightly regulated through the Ubiquitin Proteasome System (UPS). Several E3 ligases were shown to regulate p53 stability, including MDM2. Here we report that the ubiquitin E3 ligase XIAP (X-linked Inhibitors of Apoptosis) is a direct ligase for p53 and describe a novel approach for modulating the levels of p53 by targeting the XIAP pathway. Using in vivo (live-cell) and in vitro (cell-free reconstituted system) ubiquitylation assays, we show that the XIAP-antagonist ARTS regulates the levels of p53 by promoting the degradation of XIAP. XIAP directly binds and ubiquitylates p53. In apoptotic cells, ARTS inhibits the ubiquitylation of p53 by antagonizing XIAP. XIAP knockout MEFs express higher p53 protein levels compared to wild-type MEFs. Computational screen for small molecules with high affinity to the ARTS-binding site within XIAP identified a small-molecule ARTS-mimetic, B3. This compound stimulates apoptosis in a wide range of cancer cells but not normal PBMC (Peripheral Blood Mononuclear Cells). Like ARTS, the B3 compound binds to XIAP and promotes its degradation via the UPS. B3 binding to XIAP stabilizes p53 by disrupting its interaction with XIAP. These results reveal a novel mechanism by which ARTS and p53 regulate each other through an amplification loop to promote apoptosis. Finally, these data suggest that targeting the ARTS binding pocket in XIAP can be used to increase p53 levels as a new strategy for developing anti-cancer therapeutics.

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Structure‐based design and molecular profiling of Smac‐mimetics selective for cellular IAPs

Abstract: Structural data are available in the Protein Data Bank database under the accession codes 6EXW (cIAP1-BIR3/SM130 complex) and 6EY2 (XIAP-BIR3/SM114 complex).

Cited by 13 publications

References 56 publications

Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC

Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC

Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment

ARTS and small-molecule ARTS mimetics upregulate p53 levels by promoting the degradation of XIAP

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