Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

Zhu, Hongping; Li, Yi; Liu, Yue; Han, Bo

doi:10.1002/cmdc.201900410

Cited by 14 publications

(7 citation statements)

References 158 publications

(284 reference statements)

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“…155 IAPs are often up-regulated in cancers 156 and are believed to underlie the resistance of many malignant cells to chemotherapeutics. 157,158 IAP antagonists, or SMAC mimetics, have received considerable attention as potential therapeutic agents for the treatment of cancer (Table 1), 159,160 with several compounds under clinical evaluation for solid and hematologic cancers. 161 Clinical data from these studies showed that SMAC mimetics are well tolerated, display evidence of target engagement, and have a reasonable safety profile.…”

Section: ■ Iap Proteins and Antagonistsmentioning

confidence: 99%

“…The family of IAP proteins is involved in blocking and attenuating programmed cell death pathways, predominantly through modulation of the caspase cascade. , IAP proteins cIAP1, cIAP2, XIAP, and ML-IAP are directly involved in the regulation of apoptosis . IAPs are often up-regulated in cancers and are believed to underlie the resistance of many malignant cells to chemotherapeutics. , IAP antagonists, or SMAC mimetics, have received considerable attention as potential therapeutic agents for the treatment of cancer (Table ), , with several compounds under clinical evaluation for solid and hematologic cancers . Clinical data from these studies showed that SMAC mimetics are well tolerated, display evidence of target engagement, and have a reasonable safety profile .…”

Section: Iap Proteins and Antagonistsmentioning

confidence: 99%

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Cell Survival and Cell Death at the Intersection of Autophagy and Apoptosis: Implications for Current and Future Cancer Therapeutics

Bata

Cosford

2021

ACS Pharmacol. Transl. Sci.

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Autophagy and apoptosis are functionally distinct mechanisms for cytoplasmic and cellular turnover. While these two pathways are distinct, they can also regulate each other, and central components of the apoptosis or autophagy pathway regulate both processes directly. Furthermore, several upstream stress-inducing signaling pathways can influence both autophagy and apoptosis. The crosstalk between autophagy and apoptosis has an integral role in pathological processes, including those related to cancer, homeostasis, and aging. Apoptosis is a form of programmed cell death, tightly regulated by various cellular and biochemical mechanisms, some of which have been the focus of drug discovery efforts targeting cancer therapeutics. Autophagy is a cellular degradation pathway whereby cells recycle macromolecules and organelles to generate energy when subjected to stress. Autophagy can act as either a prodeath or a prosurvival process and is both tissue and microenvironment specific. In this review we describe five groups of proteins that are integral to the apoptosis pathway and discuss their role in regulating autophagy. We highlight several apoptosis-inducing small molecules and biologics that have been developed and advanced into the clinic and discuss their effects on autophagy. For the most part, these apoptosis-inducing compounds appear to elevate autophagy activity. Under certain circumstances autophagy demonstrates cytoprotective functions and is overactivated in response to chemo- or radiotherapy which can lead to drug resistance, representing a clinical obstacle for successful cancer treatment. Thus, targeting the autophagy pathway in combination with apoptosis-inducing compounds may be a promising strategy for cancer therapy.

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Section: ■ Iap Proteins and Antagonistsmentioning

confidence: 99%

Section: Iap Proteins and Antagonistsmentioning

confidence: 99%

Cell Survival and Cell Death at the Intersection of Autophagy and Apoptosis: Implications for Current and Future Cancer Therapeutics

Bata

Cosford

2021

ACS Pharmacol. Transl. Sci.

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“…Cong et al focused on the research articles of the past 15 years and clearly summarized the structural interaction between IAPs and SMAC, four generations of SMs, and representative antagonists in clinical evaluations [96]. Subsequently, Zhu et al showed detailed strategies for designing bivalent small-molecule SMs and the progress in using them to antagonize IAPs, as well as their clinical potential [97]. These latest summaries are enormously helpful to guide further study to optimize the properties of bivalent SMs to ensure good bioavailability and targeted accumulation in various types of tumors.…”

Section: Development Of Smsmentioning

confidence: 99%

Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

Zhao

Wang

Wei

et al. 2020

Cells

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Aiming to promote cancer cell apoptosis is a mainstream strategy of cancer therapy. The second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (DIABLO) protein is an essential and endogenous antagonist of inhibitor of apoptosis proteins (IAPs). SMAC mimetics (SMs) are a series of synthetically chemical compounds. Via database analysis and literature searching, we summarize the potential mechanisms of endogenous SMAC inefficiency, degradation, mutation, releasing blockage, and depression. We review the development of SMs, as well as preclinical and clinical outcomes of SMs in solid tumor treatment, and we analyze their strengths, weaknesses, opportunities, and threats from our point of view. We also highlight several questions in need of further investigation.

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“…As a result, Smac mimetics functionally disrupt the inhibitory interaction of XIAP with caspases or stimulate the E3 ubiquitin ligase activity of cIAPs leading to a reduction in canonical NF-jB-mediated survival signals and increased noncanonical NF-jB signaling resulting in autocrine TNF secretion [23,24]. Clinical use of Smac mimetics is being explored for the treatment of multiple cancers, both as a single agent or in combination with existing chemotherapeutic agents [23,25]. Although well tolerated in phase I clinical trials [26], Smac mimetics possessed limited efficacy as a singleagent therapeutic in patients with a variety of solid tumors and hematological malignancies, including triple-negative breast cancer, ovarian, primary peritoneal, fallopian tube cancer, and multiple myeloma [27].…”

Section: Targeted Approaches For Inducing Apoptosis In Cancersmentioning

confidence: 99%

Double agents of cell death: novel emerging functions of apoptotic regulators

Lamb

2020

The FEBS Journal

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Apoptosis is a highly regulated form of cell death that is required for many homeostatic and pathological processes. Recently, alternative cell death pathways have emerged whose regulation is dependent on proteins with canonical functions in apoptosis. Dysregulation of apoptotic signaling frequently underlies the pathogenesis of many cancers, reinforcing the need to develop therapies that initiate alternative cell death processes. This review outlines the convergence points between apoptosis and other death pathways with the purpose of identifying novel strategies for the treatment of apoptosis-refractory cancers. Apoptosis proteins can play key roles in the initiation, regulation, and execution of nonapoptotic death processes that include necroptosis, autophagy, pyroptosis, mPTP-mediated necrosis, and ferroptosis. Notably, recent evidence illustrates that dying cells can exhibit biochemical and molecular characteristics of more than one different type of regulated cell death. Thus, this review highlights the amazing complexity and interconnectivity of cell death processes and also raises the idea that a top-to-bottom approach to describing cell death mechanisms may be inadequate for fully understanding the means by which cells die.

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Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

Cited by 14 publications

References 158 publications

Cell Survival and Cell Death at the Intersection of Autophagy and Apoptosis: Implications for Current and Future Cancer Therapeutics

Cell Survival and Cell Death at the Intersection of Autophagy and Apoptosis: Implications for Current and Future Cancer Therapeutics

Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

Double agents of cell death: novel emerging functions of apoptotic regulators

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