Development of Peptidomimetics Targeting IAPs.
Ontology highlight
ABSTRACT:
SUBMITTER: Sharma SK
PROVIDER: S-EPMC2710984 | biostudies-other | 2006 Mar
REPOSITORIES: biostudies-other
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Project description:Apoptosis resistance is a hallmark of human cancer. Research in the last two decades has identified key regulators of apoptosis, including inhibitor of apoptosis proteins (IAPs). These critical apoptosis regulators have been targeted for the development of new cancer therapeutics. In this article, we will discuss three members of IAP proteins, namely XIAP, cIAP1 and cIAP2, as cancer therapeutic targets and the progress made in developing new cancer therapeutic agents to target these IAP proteins.
| S-EPMC3534930 | biostudies-literature
Project description:Inhibitors of apoptosis proteins (IAPs) are a highly conserved class of multifunctional proteins. Rac1 is a well-studied Rho GTPase that controls numerous basic cellular processes. While the regulation of nucleotide binding to Rac1 is well understood, the molecular mechanisms controlling Rac1 degradation are not known. Here, we demonstrate X-linked IAP (XIAP) and cellular IAP1 (c-IAP1) directly bind to Rac1 in a nucleotide-independent manner to promote its polyubiquitination at Lys147 and proteasomal degradation. These IAPs are also required for degradation of Rac1 upon CNF1 toxin treatment or RhoGDI depletion. Consistently, downregulation of XIAP or c-IAP1 by various strategies led to an increase in Rac1 protein levels in primary and tumour cells, leading to an elongated morphology and enhanced cell migration. Further, XIAP counteracts Rac1-dependent cellular polarization in the developing zebrafish hindbrain and promotes the delamination of neurons from the normal tissue architecture. These observations unveil an evolutionarily conserved role of IAPs in controlling Rac1 stability thereby regulating the plasticity of cell migration and morphogenesis.
| S-EPMC3252583 | biostudies-literature
Project description:Inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2, and XIAP (X-linked IAP) regulate apoptosis and cytokine receptor signalling, but their overlapping functions make it difficult to distinguish their individual roles. To do so, we deleted the genes for IAPs separately and in combination. While lack of any one of the IAPs produced no overt phenotype in mice, deletion of cIap1 with cIap2 or Xiap resulted in mid-embryonic lethality. In contrast, Xiap(-/-)cIap2(-/-) mice were viable. The death of cIap2(-/-)cIap1(-/-) double mutants was rescued to birth by deletion of tumour necrosis factor (TNF) receptor 1, but not TNFR2 genes. Remarkably, hemizygosity for receptor-interacting protein kinase 1 (Ripk1) allowed Xiap(-/-)cIap1(-/-) double mutants to survive past birth, and prolonged cIap2(-/-)cIap1(-/-) embryonic survival. Similarly, deletion of Ripk3 was able to rescue the mid-gestation defect of cIap2(-/-)cIap1(-/-) embryos, as these embryos survived to E15.5. cIAPs are therefore required during development to limit activity of RIP kinases in the TNF receptor 1 signalling pathway.
| S-EPMC3321198 | biostudies-literature
Project description:BackgroundInhibitors of apoptosis proteins (IAPs) are a family of antiapoptotic proteins modulating cell cycle, signal transduction and apoptosis. Dysregulated IAPs have been reported to contribute to tumor progression and chemoresistance in various cancers. However, existing studies were sporadic and only focus on one specific cancer with one particular gene in the IAPs family. A systematic investigation on the co-expression pattern, regulation frameworks on various pathways, prognostic utility on patient outcomes, and predictive value on drug sensitivity among all the IAPs across multiple tumor types was lacking.MethodsLeveraging The Cancer Genome Atlas data with comprehensive genomic characterizations on 9714 patients across 32 tumor types and the Genomics of Drug Sensitivity in Cancer data with both genomic characterizations and drug sensitivity data on >?1000 cell lines, we investigated the co-expression pattern of IAPs, their regulations of apoptosis as well as other pathways and clinical relevance of IAPs for therapeutics development.ResultsWe discovered diverse expression pattern among IAPs, varied spectrum of apoptosis regulations through IAPs and extensive regulations beyond apoptosis involving immune response, cell cycle, gene expression and DNA damage repair. Importantly, IAPs were strong prognostic factors for patient survival and tumor stage in several tumor types including brain, liver, kidney, breast and lung cancer. Further, several IAPs were found to be predictive of sensitivity to BCL-2 inhibitors (BIRC3, BIRC5, BIRC6, and BIRC7) as well as RIPK1 inhibitors (BIRC3 and BIRC6).ConclusionTogether, our work revealed the landscape of regulations, prognostic utilities and therapeutic relevance of IAPs across multiple tumor types.
| S-EPMC6975060 | biostudies-literature
Project description:Originally described in insect viruses, cellular proteins with Baculoviral IAP repeat (BIR) motifs have been thought to function primarily as inhibitors of apoptosis. The subsequent finding that a subset of IAPs that contain a RING domain have ubiquitin protein ligase (E3) activity implied the presence of other functions. It is now known that IAPs are involved in mitotic chromosome segregation, cellular morphogenesis, copper homeostasis, and intracellular signaling. Here, we review the current understanding of the roles of IAPs in apoptotic and nonapoptotic processes and explore the notion that the latter represents the primary physiologic activities of IAPs.
| S-EPMC2677451 | biostudies-literature
Project description:Deregulation of innate immune signalling and cell death form the basis of most human disease pathogenesis. Inhibitor of APoptosis (IAP) protein-family members are frequently overexpressed in cancer and contribute to tumour cell survival, chemo-resistance, disease progression and poor prognosis. Although best known for their ability to regulate caspases, IAPs also influence ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-κB. Recent advances in our understanding of the molecular mechanisms through which IAPs influence cell death and innate immune responses have provided new insights into novel strategies for treatment of cancer. In this review we discuss our current understanding of IAP-mediated NF-κB signalling, as well as elaborate on unexpected insights into the involvement of IAPs in regulating the 'Ripoptosome', a novel intrinsic cell death-inducing platform. We propose an evolutionarily conserved concept whereby IAPs function as guardians of killer platforms such as the apoptosome in Drosophila and the Ripoptosome in mammals.
| S-EPMC3252837 | biostudies-other
Project description:Chimeric antigen receptor (CAR) T cell therapy has proven highly successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrate that antagonizing Inhibitor of Apoptosis Proteins (IAPs) with the clinical smac-mimetic, birinapant, significantly enhanced the anti-tumor activity of CAR T cells in a TNF-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T cell-derived TNF. Importantly, combining CAR T cell therapy with birinapant dramatically reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrate the synergistic potential of combining CAR T cell therapy with smac-mimetics. Taken together, we identify CAR T cell-derived TNF as a potent anti-tumor effector, which can be further harnessed by smac-mimetics.
2019-02-01 | GSE124140 | GEO
Project description:Deregulated expression of members of the IAP (inhibitor of apoptosis) family has been identified in a wide variety of neoplastic cells, and synthetic IAP antagonists represent a promising novel class of chemotherapeutic agents. Early work focused on the ability of these compounds to block the caspase-inhibitory function of XIAP (X-linked IAP). However, recent studies have shown that IAP antagonists, although primarily designed to target XIAP, trigger ubiquitin-mediated degradation of two related proteins, c-IAP (cellular IAP) 1 and c-IAP2, and through this process potentiates the death of tumour cells via autocrine cellular-signalling pathways. In this context, the relative contribution of XIAP as a target of this class of compounds is unclear. In the present study, we examine the involvement of XIAP using a recently described synthetic IAP antagonist, AEG40730, and through comparison of a human XIAP-depleted tumour cell line with its isogenic wild-type control line. Treatment with nanomolar concentrations of AEG40730 resulted in the loss of both XIAP and c-IAP1 proteins, albeit with different kinetics. Although XIAP-deficient HCT116 cells retained some sensitivity to external apoptotic stimuli, the results suggest that IAP antagonists, such as AEG40730, exert their apoptosis-enhancing effects through XIAP in addition to the c-IAPs. These results indicate that IAP antagonists can target multiple IAPs to augment distinct pro-apoptotic signalling pathways, thereby revealing the potential for these compounds in cancer therapy and underscoring the promise of IAP-targeted therapies.
| S-EPMC2674510 | biostudies-literature
Project description:SUMMARY:Apoptosis is a physiological cell death process important for development, homeostasis and the immune defence of multicellular animals. The key effectors of apoptosis are caspases, cysteine proteases that cleave after aspartate residues. The inhibitor of apoptosis (IAP) family of proteins prevent cell death by binding to and inhibiting active caspases and are negatively regulated by IAP-binding proteins, such as the mammalian protein DIABLO/Smac. IAPs are characterized by the presence of one to three domains known as baculoviral IAP repeat (BIR) domains and many also have a RING-finger domain at their carboxyl terminus. More recently, a second group of BIR-domain-containing proteins (BIRPs) have been identified that includes the mammalian proteins Bruce and Survivin as well as BIR-containing proteins in yeasts and Caenorhabditis elegans. These Survivin-like BIRPs regulate cytokinesis and mitotic spindle formation. In this review, we describe the IAPs and other BIRPs, their evolutionary relationships and their subcellular and tissue localizations.
| S-EPMC139420 | biostudies-literature
Project description:We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K(i) of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.
| S-EPMC3520070 | biostudies-literature