Future Therapeutic Directions for Smac-Mimetics.
Ontology highlight
ABSTRACT:
SUBMITTER: Morrish E
PROVIDER: S-EPMC7072318 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
Future Therapeutic Directions for Smac-Mimetics.
Morrish Emma E Brumatti Gabriela G Silke John J
Cells 20200211 2
It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mito ...[more]
Similar Datasets
Project description:Although combination antiretroviral therapy is extremely effective in lowering HIV RNA to undetectable levels in the blood, HIV persists in latently infected CD4+ T-cells and persistently infected macrophages. In latently/persistently infected cells, HIV proteins have shown to affect the expression of proteins involved in the apoptosis pathway, notably the inhibitors of apoptosis proteins (IAPs), and thereby influence cell survival. IAPs, which are inhibited by endogenous second mitochondrial-derived activators of caspases (SMAC), can serve as targets for SMAC mimetics, synthetic compounds capable of inducing apoptosis. There is increasing evidence that SMAC mimetics can be used to reverse HIV latency and/or kill cells that are latently/persistently infected with HIV. Here, we review the current state of knowledge of SMAC mimetics as an approach to eliminate HIV infected cells and discuss the potential future use of SMAC mimetics as part of an HIV cure strategy.
| S-EPMC8660680 | biostudies-literature
Project description:Despite a robust inverse association between high-density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease, the development of new therapies based on pharmacologic enhancement of HDL metabolism has proven challenging. Emerging evidence suggests that static measurement of HDL levels has inherent limitations as a surrogate for overall HDL functionality, particularly with regard to the rate of flux through the macrophage reverse cholesterol transport (RCT) pathway. Recent research has provided important insight into the molecular underpinnings of RCT, the process by which excess cellular cholesterol is effluxed from peripheral tissues and returned to the liver for ultimate intestinal excretion. This review discusses the critical importance and current strategies for quantifying RCT flux. It also highlights therapeutic strategies for augmenting macrophage RCT via three conceptual approaches: 1) improved efflux of cellular cholesterol via targeting the macrophage; 2) enhanced cholesterol efflux acceptor functionality of circulating HDL; and 3) increased hepatic uptake and biliary/intestinal excretion.
| S-EPMC3315100 | biostudies-other
Project description:Peptide drug development has made great progress in the last decade thanks to new production, modification, and analytic technologies. Peptides have been produced and modified using both chemical and biological methods, together with novel design and delivery strategies, which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field. A wide variety of natural and modified peptides have been obtained and studied, covering multiple therapeutic areas. This review summarizes the efforts and achievements in peptide drug discovery, production, and modification, and their current applications. We also discuss the value and challenges associated with future developments in therapeutic peptides.
| S-EPMC8844085 | biostudies-literature
Project description:Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments.
| S-EPMC4247261 | biostudies-literature
Project description:Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system leading to demyelination and neurodegeneration. While the initial presentation is mostly characterized by a relapsing-remitting disease, patients often progress naturally after 10-15 years to a secondary-progressive disease course. Another 10-15% present with an initial, primary-progressive MS course. Pathogenic mechanisms possibly driving progression include continued compartmentalized inflammation by T- and B-lymphocytes and cells of innate immunity, oxidative stress, iron accumulation, and consecutive mitochondrial damage, altogether leading to neurodegeneration with accumulation of disability. Increasing knowledge about pathogenic mechanisms involved in progressive MS helps to design more specific and precise therapeutic approaches. Successful examples are the B-cell targeting monoclonal antibody ocrelizumab, effective in primary progressive MS, and the sphingosine-1-receptor modulator siponimod, effective in active forms of secondary-progressive MS. Apart from that, other medications such as the B-cell targeted antibody ofatumumab, cladribine due to T- and B-cell depletion, and other sphingosine-1-receptor modulators such as ozanimod and ponesimod are under development. Moreover, some therapeutic approaches in preclinical stages are under development. In this review, we will summarize the newest therapeutic development in the field of progressive MS of the last 3 years, and shed light on auspicious substances with similar mechanisms and new developments in the therapeutic pipeline, presumably supporting a bright future for progressive MS treatment.
| S-EPMC6764045 | biostudies-literature
Project description:Monoclonal therapeutic antibodies have revolutionized the treatment of cancer and other diseases. Fc engineering aims to enhance the effector functions or half-life of therapeutic antibodies by modifying their Fc regions. Recent advances in the Fc engineering of modern therapeutic antibodies can be considered the next generation of antibody therapy. Various strategies are employed, including altering glycosylation patterns via glycoengineering and introducing mutations to the Fc region, thereby enhancing Fc receptor or complement interactions. Further, Fc engineering strategies enable the generation of bispecific IgG-based heterodimeric antibodies. As Fc engineering techniques continue to evolve, an expanding portfolio of Fc-engineered antibodies is advancing through clinical development, with several already approved for medical use. Despite the plethora of Fc-based mutations that have been analyzed in in vitro and in vivo models, we focus here in this review on the relevant Fc engineering strategies of approved therapeutic antibodies to finetune effector functions, to modify half-life and to stabilize asymmetric bispecific IgGs.
| S-EPMC10610324 | biostudies-literature
Project description:Elevated activity of bone-degrading osteoclasts (OC) contributes to pathological bone degradation in diseases such as multiple myeloma. Several proinflammatory cytokines, including TNF, contribute to osteoclastogenesis. The receptor-interacting protein kinase 1 (RIPK1) regulates inflammation and cell death. It is recruited to the TNF-receptor complex, where it is ubiquitinated, and activates transcription factor NF-κB and mitogen-activated protein kinases (MAPK). Smac-mimetics (SM) is a group of drugs that block RIPK1 ubiquitination and shifts RIPK1 to activation of apoptosis or necroptosis. In this manuscript, we show that the two SM birinapant and LCL-161 reduced the number and viability of primary human OC, and induced TNF-dependent cell death in OC precursors (pre-OC). Birinapant was more cytotoxic than LCL-161 and induced predominantly apoptosis and to some degree necroptosis. Both inhibitors restrained osteoclastogenesis induced by myeloma patient bone-marrow aspirates. SM has gained attention as novel treatment strategies both for cancer and chronic inflammatory pathologies, but limited information has been available on interactions with primary human immune cells. As LCL-161 is in phase 2 clinical studies for multiple myeloma, we propose that SM might possess additional benefits in reducing bone degradation in myeloma patients. Taken together, we show that SM reduces human osteoclastogenesis, and that these compounds may represent promising drug candidates for pathological bone degradation.
| S-EPMC7895921 | biostudies-literature
Project description:Smac/DIABLO is a protein released from mitochondria into the cytosol in response to apoptotic stimuli. Smac promotes apoptosis at least in part through antagonizing inhibitor of apoptosis proteins (IAPs), including XIAP, cIAP-1, and cIAP-2. Smac interacts with these IAPs via its N-terminal AVPI binding motif. There has been an enormous interest in academic laboratories and pharmaceutical companies in the design of small-molecule Smac mimetics as potential anticancer agents. This task is particularly challenging because it involves targeting protein-protein interactions. Nevertheless, intense research has now generated potent, specific, cell-permeable small-molecule peptidomimetics and nonpeptidic mimetics. To date, two types of Smac mimetics have been reported, namely, monovalent and bivalent Smac mimetics. The monovalent compounds are designed to mimic the binding of a single AVPI binding motif to IAP proteins, whereas the bivalent compounds contain two AVPI binding motif mimetics tethered together through a linker. Studies from several groups have clearly demonstrated that both monovalent and bivalent Smac mimetics not only enhance the antitumor activity of other anticancer agents but also can induce apoptosis as single agents in a subset of human cancer cell lines in vitro and are capable of achieving tumor regression in animal models of human cancer. In general, bivalent Smac mimetics are 100-1000 times more potent than their corresponding monovalent Smac mimetics in induction of apoptosis in tumor cells. However, properly designed monovalent Smac mimetics can achieve oral bioavailability and may have major advantages over bivalent Smac mimetics as potential drug candidates. In-depth insights on the molecular mechanism of action of Smac mimetics have been provided by several independent studies. It was shown that Smac mimetics induce apoptosis in tumor cells by targeting cIAP-1/-2 for the rapid degradation of these proteins, which leads to activation of nuclear factor kappaB (NF-kappaB) and production and secretion of tumor necrosis factor alpha (TNFalpha). TNFalpha promotes formation of a receptor-interacting serine-threonine kinase 1 (RIPK1)-dependent caspase-8-activating complex, leading to activation of caspase-8 and -3/-7 and ultimately to apoptosis. For the most efficient apoptosis induction, Smac mimetics also need to remove the inhibition of XIAP to caspase-3/-7. Hence, Smac mimetics induce apoptosis in tumor cells by targeting not only cIAP-1/-2 but also XIAP. The employment of potent, cell-permeable, small-molecule Smac mimetics has yielded important insights into the regulation of apoptosis by IAP proteins. To date, at least one Smac mimetic has been advanced into clinical development. Several other Smac mimetics are in an advanced preclinical development stage and are expected to enter human clinical testing for the treatment of cancer in the near future.
| S-EPMC2676167 | biostudies-literature
Project description:Therapeutic monoclonal antibodies (mAbs) such as antibody-drug conjugates, ligand-receptor antagonists, immune checkpoint inhibitors and bispecific T cell engagers have shown impressive efficacy in the treatment of multiple human cancers. Numerous therapeutic mAbs that have been developed for myeloid neoplasms, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are currently investigated in clinical trials. Because AML and MDS originate from malignantly transformed hematopoietic stem/progenitor cells-the so-called leukemic stem cells (LSCs) that are highly resistant to most standard drugs-these malignancies frequently relapse and have a high disease-specific mortality. Therefore, combining standard chemotherapy with antileukemic mAbs that specifically target malignant blasts and particularly LSCs or utilizing mAbs that reinforce antileukemic host immunity holds great promise for improving patient outcomes. This review provides an overview of therapeutic mAbs for AML and MDS. Antibody targets, the molecular mechanisms of action, the efficacy in preclinical leukemia models, and the results of clinical trials are discussed. New developments and future studies of therapeutic mAbs in myeloid neoplasms will advance our understanding of the immunobiology of these diseases and enhance current therapeutic strategies.
| S-EPMC5968093 | biostudies-literature
Project description:Gastric cancer (GC) is a malignancy with a high incidence and mortality, and the emergence of immunotherapy has brought survival benefits to GC patients. Compared with traditional therapy, immunotherapy has the advantages of durable response, long-term survival benefits, and lower toxicity. Therefore, targeted immune cells are the most promising therapeutic strategy in the field of oncology. In this review, we introduce the role and significance of each immune cell in the tumor microenvironment of GC and summarize the current landscape of immunotherapy in GC, which includes immune checkpoint inhibitors, adoptive cell therapy (ACT), dendritic cell (DC) vaccines, reduction of M2 tumor-associated macrophages (M2 TAMs), N2 tumor-associated neutrophils (N2 TANs), myeloid-derived suppressor cells (MDSCs), effector regulatory T cells (eTregs), and regulatory B cells (Bregs) in the tumor microenvironment and reprogram TAMs and TANs into tumor killer cells. The most widely used immunotherapy strategies are the immune checkpoint inhibitor programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody, and chimeric antigen receptor T (CAR-T) in ACT, and these therapeutic strategies have significant anti-tumor efficacy in solid tumors and hematological tumors. Targeting other immune cells provides a new direction for the immunotherapy of GC despite the relatively weak clinical data, which have been confirmed to restore or enhance anti-tumor immune function in preclinical studies and some treatment strategies have entered the clinical trial stage, and it is expected that more and more effective immune cell-based therapeutic methods will be developed and applied.
| S-EPMC9549957 | biostudies-literature