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Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 3.89M | Year: 2015

Cancer is a leading health concern. There is a need to fully understand the fundamental processes underlying development of cancer. There is increasing evidence that G protein-coupled receptors (GPCRs) and their associated signalling cascades are involved in both cancer progression and metastasis. As oncogenic GPCRs are likely to be amenable to manipulation via drugs they are ideal therapeutic targets. In ONCORNET (Oncogenic Receptor Network of Excellence and Training) we propose to target two oncogenic GPCRs; the chemokine receptors CXCR4 and CXCR7. These are highly expressed in a range of tumours and yet their role in cancer progression is not well understood. We will focus on unravelling how CXCR4 and CXCR7 are or can be modulated (small molecules, pepducins, nanodies) and investigate the effects on oncogenic responses. This represents crucial knowledge that we currently do not have and yet may well provide potential leads for drug development and commercialisation. ONCORNET will bring together the leading research scientists and labs in Europe with an interest in GPCRs and 15 early stage researchers. We will employ all the latest multidisciplinary research technologies to understand the role of these GPCRs in cancer and develop CXCR4 and CXCR7 tools for diagnostic and therapeutic purposes. Importantly, developed approaches can be extrapolated to other oncogenic GPCRs. The ONCORNET consortium will offer an extensive multidisciplinary training programme to the ESRs to ensure that they can operate in todays drug discovery programmes. This will include both research (e.g. drug discovery, proteomics, imaging, modelling) and transferable (e.g. entrepreneurship, writing, media training) skill sets that is rarely offered at PhD level. We will train ESRs to develop the next generation of multidisciplinary scientists with skills that are highly demanded by many of todays employers in drug development industries.


News Article | November 1, 2016
Site: www.newsmaker.com.au

MarketStudyReport.com adds “Infectious Disease Treatment Market in China 2016-2020” new report to its research database. The report spread across 125 pages with table and figures in it. The Research analysts forecast the infectious disease treatment market in China to grow at a CAGR of 5.01% during the period 2016-2020. Infectious diseases are caused by pathogenic microorganisms such as bacteria, parasites, fungi, or viruses. They can be transmitted from one person to another through direct or indirect contact. Anti-infective drugs are used to kill (cidal) or stop the growth (static) of infectious agents. Based on target organism, anti-infective drugs can be categorized into antibacterial, antifungal, antiviral, and antiparasitic. Browse full table of contents and data tables at https://www.marketstudyreport.com/reports/infectious-disease-treatment-market-in-china-2016-2020/ Covered in this report The report covers the present scenario and the growth prospects of the infectious disease treatment market in China for 2016-2020. To calculate the market size, the report considers revenue generated from the sales of branded, generic, and off-label drugs used to treat infectious diseases. The report also considers the revenues to be generated from the sales of drugs that are expected to be launched into the market along with the decline in revenues from the patent expiries of the marketed drugs during the forecast period. The Research report, Infectious Disease Treatment Market in China 2016-2020, has been prepared based on an in-depth market analysis with inputs from industry experts. The report covers the market landscape and its growth prospects over the coming years. The report also includes a discussion of the key vendors operating in this market. Key vendors - F. Hoffmann-La Roche - Gilead Sciences - GSK - Johnson & Johnson - Merck - Pfizer Other prominent vendors - Achaogen - Actelion - Adenovir Pharma - AstraZeneca - Bayer - Biocryst - Celsus therapeutics - Cempra - Eleven Biotherapeutics - Exoxemis - Ferrer International - Griffin Discoveries - Hexima - InSite Vision - Insmed Incorporated - KaloBios Pharmaceuticals - Lytix Biopharma - Meiji Seika Pharma - Melinta Therapeutics - Moberg Pharma - NanoViricides - Nektar - NicOx - NovaBay - NovaBiotics - Ocular Therapeutix - Panoptes Pharma - Paratek Pharmaceuticals - Polichem - PTC Therapeutics - RedHill - Shire - Starpharma Holdings - Sun Pharma - Symbiomix - Tetraphase Pharmaceuticals - The Medicines Company - Theravance Biopharma - Topica Pharmaceuticals - Vertex Pharmaceuticals - Viamet Pharmaceuticals Market driver - Use of combination therapies - For a full, detailed list, view our report Market challenge - Development of drug resistant strains - For a full, detailed list, view our report Market trend - Emergence of interferon (IFN)-free therapies - For a full, detailed list, view our report Key questions answered in this report - What will the market size be in 2020 and what will the growth rate be? - What are the key market trends? - What is driving this market? - What are the challenges to market growth? - Who are the key vendors in this market space? - What are the market opportunities and threats faced by the key vendors? - What are the strengths and weaknesses of the key vendors? To receive personalized assistance write to us @ [email protected] with the report title in the subject line along with your questions or call us at +1 866-764-2150


Istyastono E.P.,VU University Amsterdam | Istyastono E.P.,Sanata Dharma University | Kooistra A.J.,VU University Amsterdam | Vischer H.F.,VU University Amsterdam | And 7 more authors.
MedChemComm | Year: 2015

We have explored the possibilities and challenges of structure-based virtual screening (SBVS) against the human histamine H4 receptor (H4R), a key player in inflammatory responses. Several SBVS strategies, employing different H4R ligand conformations, were validated and optimized with respect to their ability to discriminate small fragment-like H4R ligands from true inactive fragments, and compared to ligand-based virtual screening (LBVS) approaches. SBVS studies with a molecular interaction fingerprint (IFP) scoring method enabled the identification of H4R ligands that were not identified in LBVS runs, demonstrating the scaffold hopping potential of combining molecular docking and IFP scoring. Retrospective VS evaluations against H4R homology models based on the histamine H1 receptor (H1R) crystal structure did not give higher enrichments of H4R ligands than H4R models based on the beta-2 adrenergic receptor (β2R). Complementary prospective SBVS studies against β2R-based and H1R-based H4R homology models led to the discovery of different new fragment-like H4R ligand chemotypes. Of the 37 tested compounds, 9 fragments (representing 5 different scaffolds) had affinities between 0.14 and 6.3 μM at the H4R. © The Royal Society of Chemistry.


Kuhne S.,VU University Amsterdam | Wijtmans M.,VU University Amsterdam | Lim H.D.,Griffin Discoveries BV | Leurs R.,VU University Amsterdam | And 3 more authors.
Expert Opinion on Investigational Drugs | Year: 2011

Introduction: The histamine H 3 receptor (H 3R) plays a pivotal role in a plethora of therapeutic areas. Blocking the H 3R with antagonists/inverse agonists has been postulated to be of broad therapeutic use. Indeed, H 3R antagonists/inverse agonists have been extensively evaluated in the clinic. Areas covered: Here, we address new developments, insights obtained and challenges encountered in the clinical evaluations. For recent H 3R clinical candidates, the status and results of the corresponding clinical trial(s) will be discussed along with preclinical data. Main findings: In all, it becomes evident that clinical evaluation of H 3R antagonists/inverse agonists is characterized by mixed results. On one hand, Pitolisant has successfully passed several Phase II trials and seems to be the most advanced compound in the clinic now, being in Phase III. On the other hand, some compounds (e.g., PF-03654647 and MK-0249) failed at Phase II clinical level for several indications. Expert opinion: A challenging feature in H 3R research is the multifaceted role of the receptor at a molecular/biochemical level, which can complicate targeting by small molecules at several (pre)clinical levels. Accordingly, H 3R antagonists/inverse agonists require further testing to pinpoint the determinants for clinical efficacy and to aid in the final push towards the market. © 2011 Informa UK, Ltd.


Kool J.,VU University Amsterdam | Rudebeck A.F.,VU University Amsterdam | Fleurbaaij F.,VU University Amsterdam | Nijmeijer S.,VU University Amsterdam | And 5 more authors.
Journal of Chromatography A | Year: 2012

In the past years we developed high-resolution screening platforms involving separation of bioactive mixtures and on-line or at-line bioassays for a wide variety of biological targets with parallel mass spectrometric detection and identification. In the current research, we make a major step forward in the development of at-line bioassays by implementation of radioligand receptor binding and functional cellular assays to evaluate bioactvity and selectivity. We demonstrate a new platform for high-resolution metabolic profiling of lead compounds for functional activity and selectivity toward the human histamine H4 receptor (hH4R), a member of the large family of membrane-bound G protein-coupled receptors. In this platform analytical chemistry, cell biology and pharmacology are merged. The methodology is based on chromatographic separation of metabolic mixtures by HPLC coupled to high-resolution fractionation onto (multiple) microtiter well plates for complementary assaying. The methodology was used for efficient and rapid metabolic profiling of the drug clozapine and three selective hH4R lead compounds. With this new platform metabolites with undesired alterations in target selectivity profiles can be readily identified. Moreover, the parallel identification of metabolite structures, with accurate-mass measurements and MS/MS, allowed identification of liable metabolic 'hotspots' for further lead optimization and plays a central role in the workflow and in this study. The methodology can be easily adapted for use with other receptor screening formats. The efficient combination of pharmacological assays with analytical techniques by leveraging high-resolution at-line fractionation as a linking technology will allow implementation of comprehensive metabolic profiling in an early phase of the drug discovery process. © 2012 Elsevier B.V.


Istyastono E.P.,VU University Amsterdam | Nijmeijer S.,VU University Amsterdam | Lim H.D.,Griffin Discoveries BV | Van De Stolpe A.,VU University Amsterdam | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2011

The histamine H 4 receptor (H 4R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H 3 receptor (H 3R), two acidic residues in the H 4R binding pocket, D 3.32 and E 5.46, act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H 4R ligands. Given the symmetric distribution of these complementary pharmacophore features in H 4R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H 4R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5) -imidazolyl)propyl]isothiourea) derivatives to investigate H 4R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H 4R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H 4R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H 4R and can be used as a general approach to elucidate the structure of protein-ligand complexes. © 2011 American Chemical Society.


Coruzzi G.,University of Parma | Pozzoli C.,University of Parma | Adami M.,University of Parma | Grandi D.,University of Parma | And 4 more authors.
Experimental Dermatology | Year: 2012

The effects of the histamine H 4 receptor antagonist JNJ7777120 were evaluated in a model of acute skin inflammation induced by local application of croton oil. The influence of strain on the effect of JNJ7777120 was investigated in four different mouse strains (CD-1, NMRI, BALB/c and C57BL/6J). In CD-1 mice, JNJ777720 (30-100mg/kg subcutaneously, s.c.) exerted a dose-dependent inhibition of croton oil-induced ear inflammation and polymorphonuclear leucocyte infiltration, as confirmed by histological evaluation of ear tissues. JNJ7777120 (30-100mg/kg) did not reduce ear oedema in NMRI, BALB/c or C57BL/6J mice. The positive control, dexamethasone (2mg/kg s.c.) induced significant anti-inflammatory effects only in CD-1 and NMRI mice. In these strains, also the histamine H 1-receptor blocker pyrilamine (30mg/kg s.c.) significantly reduced ear oedema at 2h after croton oil challenge, being as effective as JNJ7777120 in CD-1 mice. Taken together, these data demonstrate that the H 4 receptor antagonist JNJ7777120 may reduce acute croton oil-induced skin inflammation as effectively as H 1 receptor blockade. However, present experiments evidenced for the first time marked strain-related differences in the JNJ7777120 pharmacological activity, which have to be carefully considered when using this ligand to characterize histamine H 4 receptor functions in murine models and translating preclinical data to clinical human settings. © 2011 John Wiley & Sons A/S.


Smits R.A.,Griffin Discoveries BV | Lim H.D.,Griffin Discoveries BV | Van Der Meer T.,Griffin Discoveries BV | Kuhne S.,VU University Amsterdam | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

The histamine H 4 receptor is a G protein-coupled receptor that has attracted much interest for its role in inflammatory and immunomodulatory functions. In our search for new H 4R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl) quinazolin-2-amine (VUF11489), as a new H 4R antagonist. Analysis of its binding kinetics at the human H 4R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120. © 2011 Elsevier Ltd. All rights reserved.


Andaloussi M.,Griffin Discoveries BV | Lim H.D.,Griffin Discoveries BV | Van Der Meer T.,Griffin Discoveries BV | Sijm M.,Griffin Discoveries BV | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H4 receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound PF-3893787 while showing good affinities at the human and rodent histamine receptors. The receptor residence time of several of these new compounds was determined for the human H4R and compared with JNJ7777120 and PF-3893787. The pyrido[3,2-d]pyrimidines showed residence times lower than JNJ7777120 but comparable to the residence time of PF-3893787. Overall, the pyrido[3,2-d]pyrimidines show an excellent in vitro profile that warrants their further investigation in relevant models of human disease. © 2013 Elsevier Ltd. All rights reserved.


Smits R.A.,Griffin Discoveries BV | Adami M.,University of Parma | Istyastono E.P.,VU University Amsterdam | Zuiderveld O.P.,VU University Amsterdam | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2010

Hit optimization of the class of quinazoline containing histamine H 4 receptor (H4R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H4R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H4R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H4R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H4R affinity and behave as inverse agonists at the human H4R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline4-amino)-N- phenylethanesulfonamide (54) (pki = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation. © 2010 American Chemical Society.

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