LXR agonists for the treatment of atherosclerosis

Liver X receptor (LXR) alpha/beta nuclear receptors are intracellular sterol sensors that regulate expression of genes controlling cholesterol absorption, excretion, catabolism and cellular efflux in target organs, including small intestine, liver and macrophages. Through co-ordination of the expression of target genes in multiple tissues, LXR agonists increase the flux of cholesterol from the periphery to the liver, where it is metabolized and excreted into the bile. Synthetic dual LXR alpha/beta agonists decrease atherosclerosis in mice, however, upregulation of lipogenic target genes and triglyceride elevation in rodents reveals a narrow therapeutic window. LXR subtype-selective agonists or LXR modulators may dissociate the anti-atherosclerotic and lipogenic effects of current dual LXR agonists.     

PPAR agonists in the treatment of atherosclerosis

Current treatment for atherosclerotic heart disease consists mainly of the administration of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or 'statin' class of drugs. Statins, which lower low-density lipoprotein cholesterol levels and have numerous other effects in the arterial wall, have shown remarkable efficacy and an exemplary safety profile in preventing both primary and secondary atherosclerotic events. These agents, however, are less effective at raising high-density lipoprotein, lowering triglycerides and decreasing insulin resistance--all of which are important targets for the prevention of ischemic vascular disease. Agonists of the peroxisome proliferator-activated receptors (PPARs) are among the most promising drug candidates to target these treatment gaps. Only PPARalpha agonists have been shown clinically to improve the outcome of atherosclerotic heart disease; however, it will only be a matter of time before we know whether compounds that modulate the function of PPARgamma and beta/delta are also efficacious at combating atherosclerosis.     

Cholesterol modulation as an emerging strategy for the treatment of Alzheimer's disease

The basis for therapeutic strategies targeting the amyloid-beta protein (Abeta) has come from studies showing that accumulation and aggregation of the Abeta within the brain is likely to cause Alzheimer's disease (AD). Along with an ever-increasing understanding of Abeta metabolism, many potential therapeutic strategies aimed at altering Abeta metabolism have emerged. Among the more intriguing targets for therapy are enzymes involved in cholesterol homeostasis, because it has been found that altering cholesterol can influence Abeta metabolism in experimental model systems, and that cholesterol-lowering agents, specifically HMG-CoA reductase inhibitors, could reduce the incidence of AD. It is likely that cholesterol influences Abeta metabolism in several ways, including altering Abeta production and perhaps altering Abeta deposition and clearance. Thus, pharmacological modulation of cholesterol levels could provide a relatively safe means to reduce Abeta accumulation in the brain, and thereby prevent or slow the development of AD.     

Current and emerging paradigms in the therapeutic management of atherosclerosis

Background: The pathogenesis of atherosclerosis lies in abnormalities in lipoprotein metabolism leading to pathological interactions with vessel walls and the release of inflammatory components, which further aggravate the disease condition. Objective: To elucidate current and emerging trends in drug discovery towards the development of new entities regulating lipoprotein metabolism and inflammatory components to combat the progression of atherosclerosis. Methods: Research/review articles in the public domain and press releases were employed. Results/conclusion: With the recent failure of torcetrapib and succinobucol, drug discovery and development efforts towards the treatment of atherosclerosis have received a big jolt and have been slowed down to certain extent. But this could be a starting point for several new mechanisms that are emerging to discover new drugs to combat the disease.     

Src kinase inhibitors: an emerging therapeutic treatment option for prostate cancer

Importance of the field: Once prostate cancer becomes castration-resistant, bone metastases are a significant problem and treatment options are limited. As a result, there is a need for more effective therapies that have antitumor and anti-bone metastatic effects. Because Src and Src-family kinases (SFKs) are involved in multiple signaling pathways central to prostate cancer development, progression, and metastasis, in addition to normal and pathologic osteoclast activities, Src inhibition represents a valid therapeutic strategy for investigation.

Areas covered in this review: Here, current treatment options for advanced prostate cancer, the preclinical rationale behind using Src inhibitors, emerging data from clinical trials of Src inhibitors in prostate cancer, and future therapeutic directions are described. Data published in peer-reviewed journals within the last 20 years or presented at recent European or American Society of Clinical Oncology conferences have been reviewed.

What the reader will gain: Readers will gain an insight into the development of therapeutic Src inhibitors, including dasatinib and saracatinib; an understanding of their effects on prostate cancer cells and the bone microenvironment; and emerging clinical data.

Take home message: Src is implicated in prostate cancer progression and metastasis, therefore treatment with Src inhibitors warrants further investigation.     

靶向鞘氨醇激酶信号通路:一种治疗血液肿瘤的新策略（英文）

1-磷酸鞘氨醇(S1P)是重要的磷脂代谢产物并介导广泛的生物学效应,包括细胞增殖、存活和迁移等。S1P在细胞内由鞘氨醇激酶(SphK)使鞘氨醇磷酸化而形成。S1P代谢的异常调节已经成为血液肿瘤发生发展的重要环节。利用抑制剂、激动剂及抗体等靶向SphK-S1P信号通路(包括S1P受体及参与合成和降解的关键酶)已经成为血液肿瘤的新治疗策略。本文综述了SphK-S1P的重要生理作用,重点阐述了其异常调节机制及其靶向治疗在血液肿瘤中病理生理过程中的重要性。首先对磷脂代谢和信号调控进行了概述,然后总结了S1P的合成、代谢、病理和生理作用、异常调节机制以及在血液肿瘤中靶向策略。另外,还讨论了靶向SphK信号通路在新药研发中的前景和重要性。     

Osteopontin: an emerging therapeutic target for anticancer therapy

Distant migration of malignant cells or metastasis is considered one of the hallmarks of tumour progression and makes cancer a most deadly disease. The elevated expression of osteopontin (OPN), a metastasis-associated small integrin-binding ligand N-linked glycoprotein family member has been observed in several cancers and, thus, this protein is considered as a potent prognostic marker during tumour progression. OPN regulates a series of signalling cascades and augments the expression of several oncogenic molecules. Therefore, understanding the molecular mechanism and the signalling pathways by which OPN promotes tumorigenesis may be helpful in designing a novel anticancer therapy. At present, the role of OPN in regulating cancer progression is the subject of intense investigation and targeting OPN might be an appropriate therapeutic strategy for the treatment of cancer. This review is focused on OPN-based anticancer therapy, which may provide a new dimension for the successful treatment of cancer.     

The immunoproteasome: an emerging therapeutic target

The proteasome, a large multisubunit protease complex, has been extensively investigated over the years, greatly enhancing our understanding of critical roles that the proteasome plays in cells. The FDA approval of bortezomib for the treatment of multiple myeloma and mantle cell lymphoma has validated the proteasome as an anticancer target. However, the undesirable toxicities of these agents limit their broad utility. The immunoproteasome, an alternative form of the constitutive proteasome, has recently been explored as a therapeutic target. While the immunoproteasome, normally expressed in cells of hematopoietic origin, has been shown to be associated with various types of cancer and inflammatory diseases, its multifaceted function is not fully understood due to the lack of appropriate molecular probes. In this review, recent advances in the immunoproteasome field are covered, including potential implications in disease states. In particular, recent developments in immunoproteasome-specific inhibitors are emphasized.     

Sphingosine-1-phosphate: an emerging therapeutic target

Sphingosine-1-phosphate (SPP) is a polar sphingolipid metabolite that has received increasing attention as both an extracellular mediator and an intracellular second messenger. SPP is the ligand of a family of specific cell surface G-protein coupled receptors (GPCR), known as the endothelial differentiation gene-1 (EDG-1) family. These receptors, which include EDG-1, -3, -5, -6 and -8, regulate diverse processes including cell migration, angiogenesis, vascular maturation, heart development, neurite retraction and soma rounding. In addition, abundant evidence indicates that SPP also acts as an intracellular lipid messenger, regulating calcium mobilisation, cell growth and survival. The relative intracellular level of SPP and ceramide, another sphingolipid metabolite associated with cell death and cell growth arrest, is an important factor in determining cell fate. Changes in SPP and ceramide have been implicated in a number of pathological conditions in which apoptosis plays an important role, including cancer and neurodegenerative disorders, as well as in atherosclerosis and allergic responses. This review will examine the biosynthesis, metabolism and potential functions of SPP in diverse diseases in order to illuminate targets for the pharmaceutical and therapeutic manipulation of SPP levels.     

丝裂原活化的蛋白激酶:一个治疗病理性痛潜在的药物新靶点

病理性痛(pathological pain)是临床上常见的疼痛,通常分为炎性痛(inflammatory pain)和神经病理性痛(neuro-pathic pain),具有痛觉过敏和痛觉异常等疼痛神经可塑性特点;丝裂原活化的蛋白激酶(mitogen-activated proteins kinases,MAPKs)作为一种关键细胞信号分子,包括细胞外信号调节激酶(ERK)、p38和c-Jun氨基末端激酶(JNK)3条主要激活通路,在病理性痛觉信号转导和神经可塑性调控中起重要作用。在不同动物模型中,抑制MAPKs信号通路,可明显减轻炎症痛和神经病理性痛,这为MAPKs抑制剂开发成为治疗病理性痛的药物提供了可能,MAPKs已成为治疗病理性痛药物作用的一个重要的潜在的靶点。     

Cytotoxic and molecular chemotherapy for high-grade glioma: an emerging strategy for the future

Maximal surgical debulking and radiotherapy have been the cornerstone of therapy for high-grade gliomas. The impact of chemotherapy on outcome has been marginal and, until recently, its usage has been debatable. The development of new drugs and an improved understanding of chemoresistance have reinvigorated interest in this treatment modality. Furthermore, increasing knowledge of gliomagenesis has also led to novel non-cytotoxic approaches to targeting the molecular machinery that is responsible for tumour development and progression. These new strategies, which are currently being evaluated in clinical trials, provide new hope for the future.     

Targeting invasion induction as a therapeutic strategy for the treatment of cancer

The spread of cancer cells from the primary tumor to a distant site involves many of the invasive processes normally required for wound healing, including migration through the local connective tissue, invasion of the vasculature, extravasation, invasion of the connective tissue at a distant site, and angiogenesis. Thus, the abilities of tumor cells to invade the host, and to induce endothelial cell invasion and neovascularization, are central to malignant progression. The plasminogen activator system, which plays a direct role in stimulating alpha5beta1 integrin fibronectin receptor-mediated invasion during wound healing, is also very important in tumor cell invasion and metastasis, as well as in angiogenesis. Therefore, the alpha5beta1 receptor and the plasminogen activator system may be promising targets for directed anticancer therapies.     

Targeting the cholinergic system as a therapeutic strategy for the treatment of pain

Acetylcholine mediates its effects through both the nicotinic acetylcholine receptors (ligand-gated ion channels) and the G protein-coupled muscarinic receptors. It plays pivotal roles in a diverse array of physiological processes and its activity is controlled through enzymatic degradation by acetylcholinesterase. The effects of receptor agonists and enzyme inhibitors, collectively termed cholinomimetics, in antinociception/analgesia are well established. These compounds successfully inhibit pain signaling in both humans and animals and are efficacious in a number of different preclinical and clinical pain models, suggesting a broad therapeutic potential. In this review we examine and discuss the evidence for the therapeutic exploitation of the cholinergic system as an approach to treat pain.     

Design, structure activity relationships and X-Ray co-crystallography of non-steroidal LXR agonists

The Liver X Receptor (LXR) alpha and beta isoforms are members of the type II nuclear receptor family which function as a heterodimer with the Retinoid X Receptor (RXR). Upon agonist binding, the formation of the LXR/RXR heterodimer takes place and ultimately the regulation of a number of genes begins. The LXR isoforms share 77% sequence homology, with LXRalpha having highest expression in liver, intestine, adipose tissue, and macrophages and LXRbeta being ubiquitously expressed. The aim of this article is to review the reported medicinal chemistry strategies towards the optimisation of novel non-steroidal chemotypes as LXR agonists. An analysis of the structural features important for LXR ligand binding will be given, utilising both structural activity relationship data obtained from LXR assays as well as X-ray co-crystallographic data obtained with LXR ligands and the LXR ligand binding domain (LBD). The X-ray co-crystallographic data analysis will detail the key structural interactions required for LXR binding/agonist activity and reveal the differences observed between chemotype classes. It has been postulated that a LXRbeta selective compound may have a beneficial outcome on the lipid profile for a ligand by dissociating the favourable and unfavourable effects of LXR agonists. Whilst there have been a few examples of compounds showing a modest level of LXRalpha selectivity, obtaining a potent LXRbeta selective compound has been more challenging. Analysis of the SAR and X-ray co-crystallographic data suggests that the rational design of a LXRbeta selective compound will not be trivial.