DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2015/0157584A1 Guan Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

US 2015O157584A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0157584A1 Guan et al. (43) Pub. Date: Jun. 11, 2015 (54) INHIBITORS OF HIPPO-YAP SIGNALING Publication Classification PATHWAY (51) Int. Cl. (71) Applicants: The Regents of the University of A613 L/15 (2006.01) O - O A613 L/44 (2006.01) California, Oakland, CA (US); The J. A 6LX3L/277 (2006.01) David Gladstone Institutes, San A613 L/45 (2006.015 Francisco, CA (US) A613 L/437 (2006.01) A 6LX39/395 (2006.01) (72) Inventors: Kun-Liang Guan, San Diego, CA (US); A613 L/522 (2006.01) Faxing Yu, San Diego, CA (US); Sheng A63/66 (2006.01) Ding, San Diego, CA (US) A638/48 (2006.01) A638/26 (2006.01) (73) Assignees: The J. David Gladstone Institutes, San A63L/38 (2006.01) Francisco, CA (US); The Regents of the A613 L/4453 (2006.01) University of California, Oakland, CA A613 L/405 (2006.01) US s s A613 L/404 (2006.01) (US) (52) U.S. Cl. CPC ............. A6 IK3 L/15 (2013.01); A61 K31/4015 (21) Appl. No.: 14/406,749 (2013.01); A61 K3I/44 (2013.01); A61 K 1-1. 3I/277 (2013.01); A61 K3I/451 (2013.01); (22) PCT Filed: May 31, 2013 A6 IK3I/437 (2013.01); A61 K3I/404 (2013.01); A61 K3I/522 (2013.01); A61 K (86). PCT No.: PCT/US2013/043752 3 1/661 (2013.01); A61 K38/4833 (2013.01): S371 (c)(1), A61K 38/26 (2013.01); A61 K3I/138 (2) Date: Dec. 9, 2014 (2013.01); A61 K3I/4453 (2013.01); A61 K 39/39558 (2013.01) (57) ABSTRACT Related U.S. Application Data This invention provides methods of preventing, reducing, (60) Provisional application No. 61/658,796, filed on Jun. delaying or inhibiting the proliferation, growth, migration 12, 2012, provisional application No. 61/658,084, and/or metastasis of cancer by administering an effective filed on Jun. 11, 2012. amount of an inhibitor of the Hippo-YAP signaling pathway. Patent Application Publication Jun. 11, 2015 Sheet 1 of 43 US 2015/O157584A1 A B is 0x. 8 (AD six Patent Application Publication Jun. 11, 2015 Sheet 2 of 43 US 2015/O157584A1 GT Patent Application Publication Jun. 11, 2015 Sheet 3 of 43 US 2015/O157584A1 ?**** H-HZ(61-I s: :: S: Patent Application Publication Jun. 11, 2015 Sheet 4 of 43 US 2015/O157584A1 . i 3888-: Fig. 3 Patent Application Publication Jun. 11, 2015 Sheet 5 of 43 US 2015/O157584A1 8A S18 8: wir s' - c. Fig. 4 Patent Application Publication Jun. 11, 2015 Sheet 6 of 43 US 2015/O157584A1 Fig. 5 Patent Application Publication Jun. 11, 2015 Sheet 7 of 43 US 2015/O157584A1 Fig. 6 Patent Application Publication Jun. 11, 2015 Sheet 8 of 43 US 2015/O157584A1 Fig. 7 Patent Application Publication Jun. 11, 2015 Sheet 9 of 43 US 2015/O157584A1 : 88:: ... as 3'x3 8883:' 's.', a 88:g {: $:8:8x8 Fig. 8 Patent Application Publication Jun. 11, 2015 Sheet 10 of 43 US 2015/O157584A1 8:38: 8:8 Fig. 9 Patent Application Publication Jun. 11, 2015 Sheet 11 of 43 US 2015/O157584A1 PA 8 . A ... :::::::: YAir cost-YA 8.*.** pias S808 :::::::: 88: *:::::::: is: Fig. 10 Patent Application Publication Jun. 11, 2015 Sheet 12 of 43 US 2015/O157584A1 Patent Application Publication Jun. 11, 2015 Sheet 13 of 43 US 2015/O157584A1 - K8x8 six 3:38 ;38 88-8: ;:YA 8. 38:::::: Y88 {x : 8:33 Y: ; : 88-8 Patent Application Publication Jun. 11, 2015 Sheet 14 of 43 US 2015/O157584A1 8. {8xxxx ::::::::::: 8: as tag six is *x8: x8: w8: 88:83. Ex8x8:8 :88. 88: ::::::::::::: gists; 38 88: *:::: W i: : presses Fig. 13 Patent Application Publication Jun. 11, 2015 Sheet 15 of 43 US 2015/O157584A1 Y888: Y888.88: 888 3r-Yar 3. x & 8 8- ::::::::8:8 ... s. 3: ... 8 Y88 8: Patent Application Publication Jun. 11, 2015 Sheet 16 of 43 US 2015/O157584A1 Reporter Exxix. Fig. 15 Patent Application Publication Jun. 11, 2015 Sheet 17 of 43 US 2015/O157584A1 105goios Cross { & s : x ::::::: Fig. 16A-D Patent Application Publication Jun. 11, 2015 Sheet 18 of 43 US 2015/O157584A1 SF288 : : & Yet is Fig. 16E-G Patent Application Publication Jun. 11, 2015 Sheet 19 of 43 US 2015/O157584A1 Fig. 16H-1 Patent Application Publication Jun. 11, 2015 Sheet 20 of 43 US 2015/O157584A1 A. Y^* Expressier is co xx:3: 883 : : Fig. 17A-C Patent Application Publication Jun. 11, 2015 Sheet 21 of 43 US 2015/O157584A1 :::::::: : Fig. 17D-E Patent Application Publication Jun. 11, 2015 Sheet 22 of 43 US 2015/O157584A1 Fig. 18 Patent Application Publication Jun. 11, 2015 Sheet 23 of 43 US 2015/O157584A1 Patent Application Publication Jun. 11, 2015 Sheet 24 of 43 US 2015/O157584 A1 s s s Patent Application Publication Jun. 11, 2015 Sheet 25 of 43 US 2015/O157584A1 Patent Application Publication Jun. 11, 2015 Sheet 26 of 43 US 2015/O157584A1 Patent Application Publication Jun. 11, 2015 Sheet 27 of 43 US 2015/O157584A1 2: 24th 38: his Fig. 21 Patent Application Publication Jun. 11, 2015 Sheet 28 of 43 US 2015/O157584A1 Cotto O3. Fig. 22A-B Patent Application Publication Jun. 11, 2015 Sheet 29 of 43 US 2015/O157584A1 Fig. 22C-D Patent Application Publication Jun. 11, 2015 Sheet 30 of 43 US 2015/O157584A1 Fig. 22E-G Patent Application Publication Jun. 11, 2015 Sheet 31 of 43 US 2015/O157584A1 : Patent Application Publication Jun. 11, 2015 Sheet 32 of 43 US 2015/O157584A1 Fig. 24 Patent Application Publication Jun. 11, 2015 Sheet 33 of 43 US 2015/O157584A1 87-V/GZ ‘61-I 6e-soud Patent Application Publication Jun. 11, 2015 Sheet 34 of 43 US 2015/O157584A1 sep XS eudoet & x : eer in a x 8: 8x: x : toe oidso Patent Application Publication Jun. 11, 2015 Sheet 35 of 43 US 2015/O157584A1 s Patent Application Publication Jun. 11, 2015 Sheet 36 of 43 US 2015/O157584A1 88-888 8-883. 838:38 F - + 8: p888-88 :8:8883 *:::::::: Fig. 26A-F Patent Application Publication Jun. 11, 2015 Sheet 37 of 43 US 2015/O157584 A1 s www.: is ex-tag (xxxi & six .ats: 3 sistix. as is 8. ... : : ::::: :::::::: *:::: Fig. 27A-E Patent Application Publication Jun. 11, 2015 Sheet 38 of 43 US 2015/O157584A1 -- Six phi C.2s. 8 3X. ph O2 888 Flag-YAP 08-tag iii. iycito YAx his phos-tag poRE8 G---. E8 0 2 5 O 2 5 K's 20 in Flag-YAP Ex3-tag AX Fig. 28A-C Patent Application Publication Jun. 11, 2015 Sheet 39 of 43 US 2015/O157584A1 Fig. 29A-C Patent Application Publication Jun. 11, 2015 Sheet 40 of 43 US 2015/O157584A1 &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&#3 Fig. 29D-F Patent Application Publication Jun. 11, 2015 Sheet 41 of 43 US 2015/O157584A1 six y Kii anneley Patent Application Publication Jun. 11, 2015 Sheet 42 of 43 US 2015/O157584A1 A. 8. s x 88: Fig. 30A-G Patent Application Publication Jun. 11, 2015 Sheet 43 of 43 US 2015/O157584A1 s Apoptosis Proliferation Fig. 31 US 2015/O157584 A1 Jun. 11, 2015 INHIBITORS OF HIPPO-YAP SIGNALING that promote proliferation and inhibit apoptosis (Zhao et al., PATHWAY Genes Dev (2008) 22:1962-1971). Phosphorylation of YAP by Lats 1/2 kinases can also promote its ubiquitination-depen CROSS-REFERENCE TO RELATED dent degradation (Zhao et al., Genes Dev (2010) 24:72-85). APPLICATIONS TAZ is a YAP paralog in mammals and is also regulated by the 0001. This application is a U.S. national phase filing under Hippo-YAP pathway through both cytoplasmic retention and 35 U.S.C. S371 of Intl. Appl. No. PCT/US2013/043752, filed proteasome degradation (Lei et al., Mol Cell Biol (2008) on May 31, 2013, which claims the benefit under 35 U.S.C. 28:2426-2436). S119(e) of U.S. Provisional Application No. 61/658,084, 0006. In transgenic mice, Yap promotes liver enlargement filed on Jun. 11, 2012, and U.S. Provisional Application No. in a reversible manner (Camargo et al., Curr Biol (2007) 61/658,796, filed on Jun. 12, 2012, which are hereby incor 17:2054-2060; Dong et al., Cell (2007) 130:1120-1133), sug porated herein in their entireties for all purposes. gesting organ size control relies on tight regulation of Hippo YAP pathway activity. Sustained YAP expression results in STATEMENT OF GOVERNMENTAL SUPPORT hyperplasia or tumor development (Dong et al., 2007, Supra), and genetic ablation of Hippo-YAP pathway components in 0002 This invention was made with government support mice also leads to tumor formation (Benhamouche et al., under Grant No. 5R01 CA132809, awarded by the National Genes Dev (2010) 24:1718-1730; Cai et al., Genes Dev Institutes of Health. The government has certain rights in the (2010) 24, 2383-2388; Lee et al., Proc Natl Acad Sci USA invention. (2010) 107:8248-8253: Lu et al., Proc Natl Acad Sci USA (2010) 107:1437-1442; Xu et al., Cancer (2009) 115:4576 FIELD OF THE INVENTION 4585; Zhang et al., Dev Cell (2010) 19:27-38; Zhou et al., 0003. The present invention relates to preventing, reduc Cancer Cell (2009) 16:425-438). Moreover, abnormal acti ing, delaying or inhibiting the proliferation, growth, migra vation of YAP and TAZ has been associated with human tion and/or metastasis of cancer by administering an effective cancers (Overholtzer et al., Proc Natl AcadSci USA (2006) amount of an inhibitor of the HIPPO-YAP signaling pathway.
Recommended publications
  • Endothelin System and Therapeutic Application of Endothelin Receptor

    Endothelin System and Therapeutic Application of Endothelin Receptor

    xperim ACCESS Freely available online & E en OPEN l ta a l ic P in h l a C r m f o a c l a o n l o r g u y o J Journal of ISSN: 2161-1459 Clinical & Experimental Pharmacology Research Article Endothelin System and Therapeutic Application of Endothelin Receptor Antagonists Abebe Basazn Mekuria, Zemene Demelash Kifle*, Mohammedbrhan Abdelwuhab Department of Pharmacology, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia ABSTRACT Endothelin is a 21 amino acid molecule endogenous potent vasoconstrictor peptide. Endothelin is synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonic, and inflammatory cells. It acts through a seven transmembrane endothelin receptor A (ETA) and endothelin receptor B (ETB) receptors belongs to G protein-coupled rhodopsin-type receptor superfamily. This peptide involved in pathogenesis of cardiovascular disorder like (heart failure, arterial hypertension, myocardial infraction and atherosclerosis), renal failure, pulmonary arterial hypertension and it also involved in pathogenesis of cancer. Potentially endothelin receptor antagonist helps the treatment of the above disorder. Currently, there are a lot of trails both per-clinical and clinical on endothelin antagonist for various cardiovascular, pulmonary and cancer disorder. Some are approved by FAD for the treatment. These agents are including both selective and non-selective endothelin receptor antagonist (ETA/B). Currently, Bosentan, Ambrisentan, and Macitentan approved
  • Supporting Online Material

    Supporting Online Material

    1 2 3 4 5 6 7 Supplementary Information for 8 9 Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic 10 retinopathy 11 12 *Samuel A. Mills, *Andrew I. Jobling, *Michael A. Dixon, Bang V. Bui, Kirstan A. Vessey, Joanna A. Phipps, 13 Ursula Greferath, Gene Venables, Vickie H.Y. Wong, Connie H.Y. Wong, Zheng He, Flora Hui, James C. 14 Young, Josh Tonc, Elena Ivanova, Botir T. Sagdullaev, Erica L. Fletcher 15 * Joint first authors 16 17 Corresponding author: 18 Prof. Erica L. Fletcher. Department of Anatomy & Neuroscience. The University of Melbourne, Grattan St, 19 Parkville 3010, Victoria, Australia. 20 Email: [email protected] ; Tel: +61-3-8344-3218; Fax: +61-3-9347-5219 21 22 This PDF file includes: 23 24 Supplementary text 25 Figures S1 to S10 26 Tables S1 to S7 27 Legends for Movies S1 to S2 28 SI References 29 30 Other supplementary materials for this manuscript include the following: 31 32 Movies S1 to S2 33 34 35 36 1 1 Supplementary Information Text 2 Materials and Methods 3 Microglial process movement on retinal vessels 4 Dark agouti rats were anaesthetized, injected intraperitoneally with rhodamine B (Sigma-Aldrich) to label blood 5 vessels and retinal explants established as described in the main text. Retinal microglia were labelled with Iba-1 6 and imaging performed on an inverted confocal microscope (Leica SP5). Baseline images were taken for 10 7 minutes, followed by the addition of PBS (10 minutes) and then either fractalkine or fractalkine + candesartan 8 (10 minutes) using concentrations outlined in the main text.
  • FY 2020 Results Conference Call and Webcast for Investors and Analysts

    FY 2020 Results Conference Call and Webcast for Investors and Analysts

    FY 2020 results Conference call and webcast for investors and analysts 11 February 2021 Forward-looking statements In order, among other things, to utilise the 'safe harbour' provisions of the US Private Securities Litigation Reform Act of 1995, AstraZeneca (hereafter ‘the Group’) provides the following cautionary statement: this document contains certain forward-looking statements with respect to the operations, performance and financial condition of the Group, including, among other things, statements about expected revenues, margins, earnings per share or other financial or other measures. Although the Group believes its expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of preparation of this document and the Group undertakes no obligation to update these forward-looking statements. The Group identifies the forward-looking statements by using the words 'anticipates', 'believes', 'expects', 'intends' and similar expressions in such statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond the Group’s control, include, among other things: the risk of failure or delay in delivery of pipeline or launch of new medicines; the risk of failure
  • Zibotentan, an Endothelin a Receptor Antagonist, Prevents Amyloid-Я

    Zibotentan, an Endothelin a Receptor Antagonist, Prevents Amyloid-Я

    Journal of Alzheimer’s Disease 73 (2020) 1185–1199 1185 DOI 10.3233/JAD-190630 IOS Press Zibotentan, an Endothelin A Receptor Antagonist, Prevents Amyloid-␤-Induced Hypertension and Maintains Cerebral Perfusion Jennifer C. Palmera,1, Hannah M. Taylera,1, Laurence Dyera, Patrick G. Kehoea, Julian F.R. Patonb and Seth Lovea,∗ aTranslational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK bDepartment of Physiology, Faculty of Medical & Health Sciences, University of Auckland, New Zealand Accepted 25 November 2019 Abstract. Cerebral blood flow is reduced in Alzheimer’s disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-␤ (A␤) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in brain tissue correlates positively with A␤ load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of A␤40 exacerbated pre- existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of A␤40 on blood pressure and heart rate and their variability; carotid flow; endothelin-1; and markers of cerebral oxygenation, in the (normotensive) Wistar rat, and the modulatory influence of the endothelin A receptor antagonist Zibotentan (ZD4054). Cerebral infusion of A␤ caused progressive rise in blood pressure (p < 0.0001) (paired t-test: increase of 3 (0.1–5.6) mmHg (p = 0.040)), with evidence of reduced baroreflex responsiveness, and accumulation of A␤ and elevated endothelin-1 in the vicinity of the infusion.
  • Experimental Models of Prostate Cancer Bone Metastasis - Establishment, Characterization and Imaging of Xenograft Bone Metastasis Models

    Experimental Models of Prostate Cancer Bone Metastasis - Establishment, Characterization and Imaging of Xenograft Bone Metastasis Models

    Experimental Models of Prostate Cancer Bone Metastasis - Establishment, characterization and imaging of xenograft bone metastasis models - PhD thesis presented by Marta Garcia López To obtain the degree of PhD for the Universitat Autònoma de Barcelona (UAB) PhD thesis done at the Research Unit in Biomedicine and Translational and Pediatrics Oncology, at the Vall d’Hebron Research Institute, Vall d’Hebron Hospital, under the supervision of Drs. Jaume Reventós i Puigjaner, Andreas Doll and Juan Morote Robles Doctoral study in Biochemistry, Molecular Biology and Biomedicine. Universitat Autònoma de Barcelona, Faculty of Bioscience, Department of Biochemistry and Molecular Biology Universitat Autònoma de Barcelona, 2013 Dr. Jaume Reventós Puigjaner Dr. Andreas Doll Dr. Juan Morote Robles Marta Garcia López No entiendes realmente algo a menos que seas capaz de explicárselo a tu abuela. Albert Einstein Summary In industrialized countries, prostate cancer (PCa) is the most common malignancy in men, but mortality rates are much lower than those recorded in developing countries, reflecting benefits from advances in early diagnosis and effective treatment. However, the metastatic disease rather than the primary tumour is responsible for much of the resulting morbidity and mortality. Skeletal metastases occur in more than 70% of cases of late-stage of PCa and they confer a high level of morbidity, a 5-year survival rate of 25% and median survival of approximately 40 months. Though fractures and spinal cord compression are potential complications, the most common symptom of bone metastases is pain. Bone metastases from PCa lead to an accelerated bone turnover state that features pathological activation of both osteoblasts and osteoclasts.
  • Tanibirumab (CUI C3490677) Add to Cart

    Tanibirumab (CUI C3490677) Add to Cart

    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD

    Supplementary Table S4. FGA Co-Expressed Gene List in LUAD

    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
  • Characterisation of Proendothelin-1 Derived Peptides and Evaluation of Their Utility As Biomarkers of Vascular and Renal Pathologies

    Characterisation of Proendothelin-1 Derived Peptides and Evaluation of Their Utility As Biomarkers of Vascular and Renal Pathologies

    Characterisation of Proendothelin-1 Derived Peptides and Evaluation of Their Utility as Biomarkers of Vascular and Renal Pathologies Jale Yuzugulen A thesis submitted for the degree of Doctor of Philosophy (Ph.D) in the Barts and the London School of Medicine and Dentistry of the Queen Mary, University of London 2014 Centre for Translational Medicine & Therapeutics, William Harvey Research Institute, John Vane Science Centre Charterhouse Square London UK i Statement of originality I, Jale Yuzugulen, confirm that the research included within this thesis is my own work or that where it has been carried out in collaboration with, or supported by others, that this is duly acknowledged below and my contribution indicated. Previously published material is also acknowledged below. I attest that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Signature: [ ] Date: 10/03/2014 ii List of publications and abstracts arising from this thesis: 1. Yuzugulen J, Wood EG, Douthwaite JA, Villar IC, Patel NS, Jegard J, Montoya A, Cutillas P, Hartley O, Ahluwalia A, Corder R.
  • Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

    Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

    biomolecules Review Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders Béla Kiss 1, István Laszlovszky 2, Balázs Krámos 3, András Visegrády 1, Amrita Bobok 1, György Lévay 1, Balázs Lendvai 1 and Viktor Román 1,* 1 Pharmacological and Drug Safety Research, Gedeon Richter Plc., 1103 Budapest, Hungary; [email protected] (B.K.); [email protected] (A.V.); [email protected] (A.B.); [email protected] (G.L.); [email protected] (B.L.) 2 Medical Division, Gedeon Richter Plc., 1103 Budapest, Hungary; [email protected] 3 Spectroscopic Research Department, Gedeon Richter Plc., 1103 Budapest, Hungary; [email protected] * Correspondence: [email protected]; Tel.: +36-1-432-6131; Fax: +36-1-889-8400 Abstract: Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome.
  • RT² Profiler PCR Array (96-Well Format and 384-Well [4 X 96] Format)

    RT² Profiler PCR Array (96-Well Format and 384-Well [4 X 96] Format)

    RT² Profiler PCR Array (96-Well Format and 384-Well [4 x 96] Format) Human GPCR Signaling PathwayFinder Cat. no. 330231 PAHS-071ZA For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 5700, 7000, 7300, 7500, Format A 7700, 7900HT, ViiA™ 7 (96-well block); Bio-Rad® models iCycler®, iQ™5, MyiQ™, MyiQ2; Bio-Rad/MJ Research Chromo4™; Eppendorf® Mastercycler® ep realplex models 2, 2s, 4, 4s; Stratagene® models Mx3005P®, Mx3000P®; Takara TP-800 RT² Profiler PCR Array, Applied Biosystems models 7500 (Fast block), 7900HT (Fast Format C block), StepOnePlus™, ViiA 7 (Fast block) RT² Profiler PCR Array, Bio-Rad CFX96™; Bio-Rad/MJ Research models DNA Format D Engine Opticon®, DNA Engine Opticon 2; Stratagene Mx4000® RT² Profiler PCR Array, Applied Biosystems models 7900HT (384-well block), ViiA 7 Format E (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (96-well block) Format F RT² Profiler PCR Array, Roche LightCycler 480 (384-well block) Format G RT² Profiler PCR Array, Fluidigm® BioMark™ Format H Sample & Assay Technologies Description The Human G-Protein-Coupled Receptor Signaling PathwayFinder RT² Profiler PCR Array profiles the expression of 84 genes representative of and involved in GPCR-mediated signal transduction pathways. G-protein Coupled Receptors (GPCRs) that are represented on this array include bioactive lipid receptors, metabotropic glutamate receptors (mGluRs), GABA-B-like receptors, rhodopsin-like receptors, and secretin-like receptors. Members of the intricate network of intracellular signaling pathways involved in GPCR-mediated signal transduction are also represented on this array including the cAMP / PKA Pathway, Calcium / PKC Pathway, Calcium / NFAT Pathway, PLC Pathway, Protein Tyrosine Kinase Pathway, PKC / MEK Pathway, p43 / p44MAP Pathway, p38 MAP Pathway, PI-3 Kinase Pathway, NO-cGMP Pathway, Rho Pathway, NFκB Pathway and Jak / Stat Pathway.
  • Guide to Prescription Drug Benefits — NF-681

    Guide to Prescription Drug Benefits — NF-681

    GUIDE TO PRESCRIPTION DRUG BENEFITS Capital BlueCross is an Independent Licensee of the BlueCross BlueShield Association TABLE OF CONTENTS 1 Contact Us — Phone Number — Website 2-3 Using Your Prescription Drug Benefit — Retail, Mail Order, and Specialty Pharmacy 4 Be a Wise Health Care Consumer/Know Your Formulary Options — Generic Preferred — Generic Non-preferred — Brand Preferred — Brand Non-preferred 5 Accessing Your Prescription Drug Information — Website Information 6 Online Tools 7-9 Preferred Medication List 10-11 Prior Authorization 12-13 Enhanced Prior Authorization (Step Therapy) 14-17 Drug Quantity Management Program 17 Generic Substitution Program 18-19 Accredo® Health Group, Inc./Specialty Medications (self-administered) — Getting Started — Specialty Medication List 20 Capital BlueCross Pharmacy Network 21 Drug Watch for 2014 — Generic — Specialty Guide to Prescription Drug Benefits Welcome to the Capital BlueCross prescription drug program. To help you understand how your prescription drug benefit works and how you can get the most out of your health care dollar, we have created this guide. If you need more information, please refer to your Certificate of Coverage, or visit our website at capbluecross.com. Contact Information Customer Service Visit the Web If you have questions about your prescription drug Visit the Capital BlueCross website at capbluecross benefit, contact CVS Caremark customer service at .com to learn more about your prescription drug 800.585.5794 (TTY: 866.236.1069). CVS Caremark benefit. There you can: pharmacists and customer service representatives — Download the most up-to-date versions of are available any time of the day, seven days a week. the Formulary, Preferred Medication List, Prior The CVS Caremark customer service team also offers Authorization Program, the Drug Quantity interpretive services in 140 languages, including in- Management Program, and other useful house, Spanish-speaking representatives.
  • GPCR/G Protein

    GPCR/G Protein

    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.