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Targeting IAP proteins for therapeutic intervention in cancer

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TLDR
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.
Abstract
Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases - pro-apoptotic executioner proteases - whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes are associated with various malignancies. 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. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.

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Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Lorenzo Galluzzi, +186 more
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
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Targeting apoptosis in cancer therapy

TL;DR: The main pathways that regulate apoptosis as well as other signalling pathways that interact with them are presented, highlighting actionable molecular targets for anticancer therapy and an overview of therapeutic agents exploiting apoptosis currently in clinical translation and known mechanisms of resistance to these agents are provided.
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Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.

TL;DR: The past 20 years have seen many advances in understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets.
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Ubiquitination in disease pathogenesis and treatment

TL;DR: The role of ubiquitination in the onset and progression of cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infection and muscle dystrophies is described and how current knowledge could be exploited for the development of new clinical therapies is indicated.
References
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Journal ArticleDOI

Hallmarks of cancer: the next generation.

TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
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Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
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Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.

TL;DR: The identification of a novel protein, Smac, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway and increases cells' sensitivity to apoptotic stimuli is reported.
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Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins

TL;DR: DIABLO (direct IAP binding protein with low pI) is a novel protein that can bind MIHA and can also interact with MIHB and MIHC and the baculoviral IAP, OpIAP.
Journal ArticleDOI

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

TL;DR: A functional classification of cell death subroutines is proposed that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic programmed cell death, regulated necrosis, autophagic cell death and mitotic catastrophe.
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