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International audience; Cancer is the second leading cause of death with tens of millions of people diagnosed with cancer every year around the world. Most radio- and chemotherapies aim to eliminate cancer cells, notably by causing severe damage to the DNA. However, efficient repair of such damage represents a common mechanism of resistance to initially effective cytotoxic agents. Thus, development of new generation anticancer drugs that target DNA repair pathways, and more particularly the base excision repair (BER) pathway that is responsible for removal of damaged bases, is of growing interest. The BER pathway is initiated by a set of enzymes known as DNA glycosylases. Unlike several downstream BER enzymes, DNA glycosylases have so far received little attention and the development of specific inhibitors of these enzymes has been lagging. Yet, dysregulation of DNA glycosylases is also known to play a central role in numerous cancers and at different stages of the disease, and thus inhibiting DNA glycosylases is now considered a valid strategy to eliminate cancer cells. This review provides a detailed overview of the activities of DNA glycosylases in normal and cancer cells, their modes of regulation, and their potential as anticancer drug targets.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs.

International audience; Introduction:Mitogen-activated protein kinase (MAPK) pathway is known to be involved in the tumorigenesis of cancer cells including non-small cell lung cancer (NSCLC) and kinases involved in this pathway are frequently mutated. The development of new targeted therapies in cancer has led to the evaluation of MEK-inhibitors. Areas covered: This article reviews different studies using trametinib alone, in combination with other targeted therapies or associated with other non-targeted therapies in NSCLC, with a focus on KRAS mutant and BRAF mutant NSCLC. Expert commentary: Trametinib demonstrated activity in association with a BRAF inhibitor when BRAF was mutated. The combination of trametinib and dabrafenib has been approved for this population of BRAF mutant NSCLC patients. For KRAS mutant NSCLC, the combination of trametinib with chemotherapy has showed promising results and should be further assessed. Several clinical trials are ongoing, assessing trametinib in combination with other targeted therapies. In addition, preclinical studies suggest a synergistic effect of trametinib in combination with immune checkpoint inhibitors and such combinations should be studied in clinical trials.

International audience; Inhibitors of the receptor tyrosine kinase (RTK) MET have been ineffective at treating cancer, possibly because of lack of knowledge that would allow selection of tumors likely to respond to this treatment. In contrast, specific epidermal growth factor receptor (EGFR) inhibitors have been used successfully against lung tumors displaying activating mutations in the kinase domain of EGFR. Recent publications describe a set of mutations causing MET exon 14 skipping, and importantly, several case reports describe objective responses to MET-targeting tyrosine kinase inhibitors in patients with such mutations. These observations suggest a novel therapeutic strategy for fighting cancer, especially in the lung. Exon 14 encodes the MET juxtamembrane domain targeted by mechanisms that negatively regulate receptor stability and activity. In this review, we describe the molecular mechanisms leading first to exon 14 skipping and then to activation of the MET receptor and how this process differs from that triggered by classical RTK-activating mutations in the kinase domain. We detail the clinical characteristics of patients carrying these mutations and the sensitivity of their tumors to MET inhibitors. Lastly, we discuss future challenges related to MET mutations in cancers, including patient screening and anticipating resistance to MET inhibitors.

International audience; Muscular dystrophies are a group of genetically distinct diseases for which no treatment exists. While gene transfer approach is being tested for several of these diseases, such strategies can be hampered when the size of the corresponding complementary DNA (cDNA) exceeds the packaging capacity of adeno-associated virus vectors. This issue concerns, in particular, dysferlinopathies and titinopathies that are due to mutations in the dysferlin (DYSF) and titin (TTN) genes. We investigated the efficacy of RNA trans-splicing as a mode of RNA therapy for these two types of diseases. Results obtained with RNA trans-splicing molecules designed to target the 3' end of mouse titin and human dysferlin pre-mRNA transcripts indicated that trans-splicing of pre-mRNA generated from minigene constructs or from the endogenous genes was achieved. Collectively, these results provide the first demonstration of DYSF and TTN trans-splicing reprogramming in vitro and in vivo. However, in addition to these positive results, we uncovered a possible issue of the technique in the form of undesirable translation of RNA pre-trans-splicing molecules, directly from open reading frames present on the molecule or associated with internal alternative cis-splicing. These events may hamper the efficiency of the trans-splicing process and/or lead to toxicity.

International audience; Being external, the fungal cell wall plays a crucial role in the fungal life. By covering the underneath cell, it offers mechanical strength and acts as a barrier, thus protecting the fungus from the hostile environment. Chemically, this cell wall is composed of different polysaccharides. Because of their specific composition, the fungal cell wall and its underlying plasma membrane are unique targets for the development of drugs against pathogenic fungal species. The objective of this review is to consolidate the current knowledge on the antifungal drugs targeting the cell wall and plasma membrane, mainly of Aspergillus and Candida species - the most prevalent fungal pathogens, and also to present challenges and questions conditioning the development of new antifungal drugs targeting the cell wall.

International audience; Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

International audience; Over the past 2 years, more than 1300 manuscripts have been published on glucagon-like peptide-1 (GLP-1) and yet, what do we know about it for sure? The European Club for the Study of GLP-1 (EuCSGLP-1) has debated the latest controversies concerning GLP-1, including both fundamental and clinical aspects, and concluded that the control of glucose metabolism by GLP-1 requires paracrine activation of the enteric nervous system to regulate numerous physiological functions. This involves-but is not limited to-the endocrine pancreas, liver, cardiovascular system, gastric-emptying and the brain. For this reason, the role of GLP-1 as an endocrine hormone has come under question. As systemic concentration of the peptide was not thought to be relevant to its physiological action, it was proposed that dipeptidyl peptidase-4 (DPP4) inhibitors would involve the control of enteric, rather than circulating, DPP4 activity to effectively regulate glycaemia. In any case, the concomitant insulinotropic and glucagonostatic roles of GLP-1 were believed to be of equal importance to glucose control. Another important question was related to the role of GLP-1 on beta cell apoptosis, regeneration and differentiation in type 2 diabetic patients. Although evidence in vitro showed that GLP-1 controls these functions, such effects remain elusive in humans in vivo. Nevertheless, the consensus was that GLP-1 could control glucose responsiveness, one of the first impaired physiological functions at the onset of diabetes. The therapeutic efficiency of GLP-1 would be related to the initial restoration of glucose competence, while an increase of beta cell mass has not yet been demonstrated. From a clinical and fundamental point of view, it was concluded that, at the onset of diabetes, an initial triggering of GLP-1 secretion-by metformin coupled with a DPP4 inhibitor-would help to activate the gut-peripheral axis and, hence, restore adequate regulation of glycaemia. GLP-1 analogues would certainly be helpful in association with long-acting insulin (albeit off-label) in patients with impaired beta cells and GLP-1 secretory potential. However, a reliable and routine feasible test to systematically assess dynamic insulin secretion is essential. More important, factors that influence therapeutic response, such as compliance and lifestyle, as well as pharmacokinetics and dosing, disease duration, age, gender, ethnicity, patients' clinical characteristics, autonomic nervous system integrity and genotype characteristics also need to be considered. A few innovative perspectives have been debated, such as the recently discovered cardiovascular protective effects of the native GLP-1 peptide and its degradation product GLP-1(9-36), as well as the neuroprotection offered by GLP-1. Although still considered speculative, these perspectives remain hopeful and promising.

International audience; Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cancer

> Le virus de la rougeole est un virus hautement contagieux transmis par aerosol. Le recepteur qui permet l’entree et la propagation du virus dans l’organisme est connu : il s’agit de SLAM (pour signaling lymphocyteactivation molecule), une molecule exclusivement exprimee par les cellules du systeme immunitaire, expliquant le tropisme du virus de la rougeole. Cependant, aux etapes tardives de l’infection, le virus doit se repliquer dans les cellules epitheliales afin de sortir de l’organisme et d’assurer sa transmission. La nature du recepteur epithelial du virus de la rougeole, longtemps restee inconnue, vient d’etre elucidee. Il s’agit de la nectine-4, une proteine qui, physiologiquement, est preferentiellement exprimee au niveau de l’appareil respiratoire, mais l’est aussi a des niveaux eleves dans certains cancers [15]. Cette avancee permet de mieux comprendre la biologie du virus de la rougeole et ouvre aussi de nouvelles perspectives dans le cadre des virotherapies oncolytiques comme deux autres textes le discutent dans ce numero (➜) [16, 17].

International audience; In 1984, the Met receptor and its ligand, the HGF/SF, were discovered thanks to their ability to induce cell transformation and proliferation. Thirty years of research highlighted their crucial role in the development and homeostasis of various structures, including many epithelial organs. This period also allowed unraveling the structural basis of their interaction and their complex signaling network. In parallel, Met was shown to be deregulated and associated with a poor prognosis in many cancers. Met involvement in resistance to current therapies is also being deciphered. Based on these data, pharmaceutical companies developed a variety of Met inhibitors, some of which are evaluated in phase III clinical trials. In this review, we trace the exemplary track record of research on Met receptor, which allowed moving from bench to bedside through the development of therapies targeting its activity. Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Met-targeted therapies.; En 1984, le récepteur à activité tyrosine kinase Met et son ligand l’HGF (hepatocyte growth factor)/SF (scatter factor) sont découverts grâce à leur aptitude à induire la transformation et la prolifération cellulaires. Trois décennies ont permis de mettre en évidence leur rôle fondamental dans le déve­loppement et l’homéostasie de nombreuses structures, notamment des organes épithéliaux. Cette même période a permis de décrypter les bases structurales de leur interaction, ainsi qu’un réseau de signalisation complexe. Parallèlement, l’implication de la dérégulation de Met dans la tumorigenèse, supposée dès sa découverte, a été démontrée ; elle est associée à un mauvais pronostic dans de nombreux cancers. Le rôle de cette dérégulation dans des phénomènes de résistance aux thérapies actuelles commence également à être déchiffré. Sur la base de ces données, des compagnies pharmaceutiques ont développé une grande diversité d’inhibiteurs ciblant l’HGF/SF ou le récepteur Met, dont certains sont actuellement évalués dans des essais cliniques de phase III. Nous proposons dans cette revue de retracer le parcours exemplaire des recherches sur le récepteur Met, qui auront permis en trente ans de passer de la découverte fondamentale d’un oncogène au développement de thérapies ciblant son action. Cependant, de nombreuses questions restent en suspens. Par exemple, l’implication de Met dans plusieurs étapes du développement reste à préciser, de même que les mécanismes faisant de ce récepteur un facteur de résistance aux traitements actuels ou le développement probable de résistances aux thérapies ciblant sa propre activité.

International audience; PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, noncatalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules.

International audience; The Smoothened (Smo) receptor is a key transducer of the Hedgehog (Hh) signaling pathway, which plays a critical role in tissue maintenance and repair. Recent studies have highlighted the therapeutic value of Smo antagonists for treating Hh-linked cancers. Research on Smo agonists indicates that these molecules are important not only for delineating canonical versus noncanonical Hh signaling but also for understanding the role of Smo in physiological and pathological conditions. This review provides an update on the potential therapeutic importance of Smo modulators, and unravels the increasing complexity of its pharmacology with regard to clinical implications.

International audience; Rationale:The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets.; Objective:The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms.; Method:Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions.; Results:The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity.; Conclusions:ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.

In 1984, the Met receptor and its ligand, the HGF/SF, were discovered thanks to their ability to induce cell transformation and proliferation. Thirty years of research highlighted their crucial role in the development and homeostasis of various structures, including many epithelial organs. This period also allowed unraveling the structural basis of their interaction and their complex signaling network. In parallel, Met was shown to be deregulated and associated with a poor prognosis in many cancers. Met involvement in resistance to current therapies is also being deciphered. Based on these data, pharmaceutical companies developed a variety of Met inhibitors, some of which are evaluated in phase III clinical trials. In this review, we trace the exemplary track record of research on Met receptor, which allowed moving from bench to bedside through the development of therapies targeting its activity. Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Met-targeted therapies., En 1984, le récepteur à activité tyrosine kinase Met et son ligand l’HGF (hepatocyte growth factor)/SF (scatter factor) sont découverts grâce à leur aptitude à induire la transformation et la prolifération cellulaires. Trois décennies ont permis de mettre en évidence leur rôle fondamental dans le déve­loppement et l’homéostasie de nombreuses structures, notamment des organes épithéliaux. Cette même période a permis de décrypter les bases structurales de leur interaction, ainsi qu’un réseau de signalisation complexe. Parallèlement, l’implication de la dérégulation de Met dans la tumorigenèse, supposée dès sa découverte, a été démontrée ; elle est associée à un mauvais pronostic dans de nombreux cancers. Le rôle de cette dérégulation dans des phénomènes de résistance aux thérapies actuelles commence également à être déchiffré. Sur la base de ces données, des compagnies pharmaceutiques ont développé une grande diversité d’inhibiteurs ciblant l’HGF/SF ou le récepteur Met, dont certains sont actuellement évalués dans des essais cliniques de phase III. Nous proposons dans cette revue de retracer le parcours exemplaire des recherches sur le récepteur Met, qui auront permis en trente ans de passer de la découverte fondamentale d’un oncogène au développement de thérapies ciblant son action. Cependant, de nombreuses questions restent en suspens. Par exemple, l’implication de Met dans plusieurs étapes du développement reste à préciser, de même que les mécanismes faisant de ce récepteur un facteur de résistance aux traitements actuels ou le développement probable de résistances aux thérapies ciblant sa propre activité.

International audience; Chemotherapy is frequently used to treat primary or metastatic cancers, but intrinsic or acquired drug resistance limits its efficiency. Sphingolipids are important regulators of various cellular processes including proliferation, apoptosis, differentiation, angiogenesis, stress, and inflammatory responses which are linked to various aspects of cancer, like tumor growth, neoangiogenesis, and response to chemotherapy. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative and proapoptotic functions, whereas sphingosine-1-phosphate and other derivatives have opposing effects. Among the variety of enzymes that control ceramide generation, acid or neutral sphingomyelinases and ceramide synthases are important targets to allow killing of cancer cells by chemotherapeutic drugs. On the contrary, glucosylceramide synthase, ceramidase, and sphingosine kinase are other targets driving cancer cell resistance to chemotherapy. This chapter focuses on ceramide-based mechanisms leading to cancer therapy sensitization or resistance which could have some impacts on the development of novel cancer therapeutic strategies.

International audience; Parkinson's disease is characterized by a triad of cardinal motor symptoms (bradykinesia, rigidity and tremor) resulting from the loss of dopaminergic neurons in the substantia nigra. This synucleinopathy is classified in the larger group of Lewy body disorders. Currently, these symptoms are relatively well alleviated by drugs that restore dopaminergic neurotransmission, andlor by deep brain stimulation. It is not yet possible to halt the underlying degeneration, or to treat symptoms due to non-dopaminergic neuron damage. This review examines the mechanisms of neuronal degeneration in Parkinson's disease, new targets for neuroprotection, and the mechanisms causing symptoms resistant to current treatments.

International audience; The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by ''RTK swapping'' by interfering with PDGFRb phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.

The purpose of this special edition of Hormones & Cancer is to relay the exciting new developments in the adrenal cancer field that have emerged in the last few years. The very successful 3rd International Adrenal Cancer Symposium: From Molecular Pathogenesis to Clinical Outcome held in Wurzburg, Germany earlier this year served as a backdrop for this project. This meeting followed two highly stimulating International Adrenal Cancer Symposia organized in Ann Arbor (Michigan, USA) and continued to be a key event in the field of adrenal cancer. More than 140 clinicians and investigators from 17 different countries attended the meeting with more than 30 talks covering the whole spectrum of this rare disease. However, rather than compile manuscripts as simple summaries of the symposium to serve as a “proceeding”, we elected to solicit bona fide state of the art “expert reviews” of various aspects of scientific and clinical import in the field of adrenal cancer. All articles were peer reviewed by experts in the endocrine, oncology, and specialized adrenal cancer field. Serendipitously, we were simultaneously given the opportunity to serve as guest editors for two separate “special editions” in both the Endocrine Society/Springer journal Hormones & Cancer and the Elsevier journal Molecular and Cellular Endocrinology. We elected to publish the more clinically relevant articles in Hormones & Cancer and the more basic articles in Molecular and Cellular Endocrinology. Readers should consider these two publications’ companion editions that detail the state of the science and clinical care pertinent to this disease. In Hormones & Cancer, articles are focused on the topics of “Advances in the diagnostic and prognostic markers of adrenocortical carcinoma” (including contributions by Auchus, Papotti et al., Young, Hahner and Sundin, and Deandreis et al.) and “Current and emerging therapies for adrenocortical carcinoma” (with contributions by Baudin et al., Porpiglia et al., Berruti et al., and Demeure et al.). In the companion Molecular and Cellular Endocrinology —Adrenal Cancer: Scientific Advances Special Edition, articles provide a comprehensive view from “Adrenal development—implications for tumorigenesis” (contributions from Simon and Hammer, Gardiner et al., Lauter et al., and de Joussineau et al.) to the “Epidemiology of adrenocortical carcinoma” (contributions by Ribeiro et al., Figueiredo et al., and Almeida and Faria), “Cellular and animal models for adrenocortical carcinoma” (contributions by Wang and Rainey, Else, Luconi and Mannelli, and Wilson and Beuschlein) and “Genetics and genomics of adrenocortical carcinoma” (contributions by Berthon et al., Ribeiro and Latronico, Wasserman et al., Assie et al., and Singh et al.). The editors would like to thank Lisa K. Byrd for her administrative efforts through this process. Together with the companion Adrenal Cancer Special Edition published in Molecular and Cellular Endocrinology, she kept 102 authors informed and on task, handling a total of 25 manuscripts. Without her involvement, this special edition would not have been possible. We hope you will enjoy reading those papers as much as we did while preparing the journal issues.

International audience; INTRODUCTION: The presence of fibrosis is associated with alterations in organ architecture and is responsible for the morbidity of diseases including pneumopathies, systemic sclerosis, liver cirrhosis, chronic cardiovascular diseases, progressive kidney diseases and diabetes. Although a growing number of pro-fibrotic molecules, mediators and other pathways have been reported, there are currently very few antifibrotic molecules being evaluated in clinical trials. AREAS COVERED: Current knowledge about the contribution of lysophosphatidic acid (LPA), a bioactive mediator acting via specific G-protein coupled receptors (LPAR), in the etiology of fibrosis. In a number of organs, fibrosis is associated with increased LPA production as well as with increased expression of some LPAR subtypes (mainly LPA1R). LPAR(-/-) knockout mice and treatment of animal models with specific antagonists clearly demonstrate the contribution of LPA1R subtype to the development of kidney, lung, vascular and dermal fibrosis. The involvement of LPA in liver fibrosis is also strongly suspected but still unproven. EXPERT OPINION: Experiments in animal models clearly demonstrate that LPA1R antagonists have interesting anti-fibrotic potencies. This reveals promising perspectives for the design of new therapeutic approaches to prevent fibrosis-associated diseases. Nevertheless, the number of efficient LPA1R antagonists currently available is still low, and none of them has been used in clinical trials so far.

International audience; This review describes the breast cancer resistance protein ABCG2 through its structure, functional roles and involvement in cell multidrug resistance, especially in cancer cells resistance to chemotherapeutics. The different types of known inhibitors are described, some being non-selective, since they also bind to other targets, and others being quite specific such as flavonoids. The different classes of active flavonoids and other polyphenols are described, some as plant natural compounds, but most of them being prepared and derivatized through medicinal chemistry. Quantitative structure-activity relationships of the ability of flavones, chalcones, xanthones, acridones and various benzopyrane/benzofurane derivatives to inhibit ABCG2-mediated drug efflux have led to pharmacophores and molecular models allowing to optimize the available hit compounds and to design new-generation lead compounds. Interestingly, inhibitory flavonoids are quite specific for ABCG2 versus ABCB1 and ABCC1, and appear either non-competitive or partially competitive towards mitoxantrone efflux. Most compounds do not inhibit ATPase activity, and are assumed not to be transported themselves by the transporter. Some acridones, firstly optimized in vitro as potent inhibitors, are indeed efficient in vivo, against human xenografts in SCID mice, more efficiently than gefitinib taken as a control. Future developments should open the way to more efficient/targeted modulators including (i) the potential interest of bimodulation by combining two different inhibitors, (ii) computer-assisted ligand-based drug design for getting more potent and more specific inhibitors, (iii) structure-based drug design from ABCG2 molecular models allowing in silico screening and docking of new inhibitors.

International audience; The study of infectious disease concerns the interaction between the host species and a pathogen organism. The analysis of such complex systems is improving with the evolution of high-throughput technologies and advanced computational resources. This article reviews integrative, systems-oriented approaches to understanding mechanisms underlying infection, immune response and inflammation to find biomarkers of disease and design new drugs. We focus on the systems biology process, especially the data gathering and analysis techniques rather than the experimental technologies or latest computational resources.

International audience; During the early phases of development, adrenal glands share a common origin with kidneys and gonads. The action of diverse transcription factors, signalling pathways and endocrine signals is required for the individualization of the adrenal primordium and its subsequent differentiation into an adult adrenal gland, with massive remodelling taking place around the time of birth in humans. Here I summarize the most important steps by which the adrenal cortex is shaped and present an overview of the current understanding of the genes and molecular pathways implicated in adrenal development and involved in the pathogenesis of its congenital diseases. Evidence is accumulating that some pivotal factors acting during adrenocortical development also play an important role to regulate the growth of adrenocortical tumors, representing promising therapeutical targets for a biology-oriented therapy.