+

WO1997035195A1 - Procede d'identification in vitro de modulateurs de membres de la superfamille des recepteurs des steroides ou thyroides - Google Patents

Procede d'identification in vitro de modulateurs de membres de la superfamille des recepteurs des steroides ou thyroides Download PDF

Info

Publication number
WO1997035195A1
WO1997035195A1 PCT/US1997/004315 US9704315W WO9735195A1 WO 1997035195 A1 WO1997035195 A1 WO 1997035195A1 US 9704315 W US9704315 W US 9704315W WO 9735195 A1 WO9735195 A1 WO 9735195A1
Authority
WO
WIPO (PCT)
Prior art keywords
complex
activator
receptors
contacting
suppressor
Prior art date
Application number
PCT/US1997/004315
Other languages
English (en)
Inventor
Ronald M. Evans
Barry M. Forman
Original Assignee
The Salk Institute For Biological Studies
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Salk Institute For Biological Studies filed Critical The Salk Institute For Biological Studies
Priority to AU23324/97A priority Critical patent/AU2332497A/en
Publication of WO1997035195A1 publication Critical patent/WO1997035195A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/743—Steroid hormones
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/723—Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor

Definitions

  • the present invention relates to intracellular receptors, and modulators therefor.
  • the present invention relates to methods for the identification of compounds which function as modulators for intracellular receptors.
  • the present invention relates to methods for the identification of compounds which activate intracellular receptors.
  • the present invention relates to methods for the identification of compounds which suppress activation of intracellular receptors.
  • HREs hormone response elements
  • exogenous inducers i.e., naturally occurring (or synthetic) inducers
  • exogenous suppressors i.e., naturally occurring (or synthetic) suppressors
  • the identification of compounds which directly or indirectly interact with intracellular receptors, and thereby affect transcription of hormone-responsive genes would be of significant value, e.g. , for therapeutic applications.
  • modulators for these novel receptors can not readily be identified. Accordingly, methods for the ready identification of modulators for such receptors would be of great value. Of particular value would be in vitro methods which can be carried out on large scale, thereby facilitating the screening of large numbers of compounds.
  • some intracellular receptors function to regulate transcription only when associated with additional transcriptionally active components, such as another member of the steroid/thyroid superfamily of receptors (i.e., as a heteromer, typically a heterodimer) .
  • additional transcriptionally active components such as another member of the steroid/thyroid superfamily of receptors (i.e., as a heteromer, typically a heterodimer) .
  • the availability of compounds which are modulators of heterodimer formation and/or activity are of great interest.
  • Modulators identified employing invention methods are capable of activating a receptor species in the presence of a heterodimerizing partner therefor, or of disrupting the activity of a receptor species in the presence or absence of a heterodimerizing partner therefor.
  • methods for the large scale identification of modulators for a single member of the steroid/thyroid superfamily of receptors comprising: individually contacting each of a plurality of test compounds with said member, wherein said member is optionally associated with one or more of a heteromeric partner therefor, a co-activator (or co-suppressor) , and/or a hormone response element, assaying for the formation or disruption of a complex comprising at least said test compound and said member, and identifying as modulators those compounds which participate in the formation or disruption of said complex.
  • methods for the large scale screening of a collection of members of the steroid/thyroid superfamily of receptors to identify those member(s) of said collection for which a given test compound may serve as a modulator comprising: individually contacting each of a plurality of said members with a test compound, wherein said members are optionally associated with one or more of a heteromeric partner therefor, a co-activator (or co-suppressor) , and/or a hormone response element, assaying for the formation or disruption of a complex comprising at least said test compound and said member, and identifying as modulators those compounds which participate in the formation or disruption of said complex.
  • any member of the steroid/thyroid superfamily of receptors can be used in the assays of the invention.
  • the phrase "members of the steroid/thyroid superfamily of receptors" refers to hormone binding proteins that operate as ligand-dependent transcription factors, including identified members of the steroid/thyroid superfamily of receptors for which specific modulators have not yet been identified (referred to hereinafter as "orphan receptors" . These hormone binding proteins have the intrinsic ability to bind to specific DNA sequences. Following binding, the transcriptional activity of target gene (i.e., a gene associated with the specific
  • DNA sequence is modulated as a function of the compound bound to the receptor.
  • DNA-binding domains of all of these nuclear receptors are related, consisting of 66-68 amino acid residues, and possessing about 20 invariant amino acid residues, including nine cysteines.
  • a member of the superfamily can be identified as a protein which contains the above-mentioned invariant amino acid residues, which are part of the DNA-binding domain of such known steroid receptors as the human glucocorticoid receptor (amino acids 421-486) , the estrogen receptor (amino acids 185-250) , the mineralocorticoid receptor (amino acids 603-668) and the human retinoic acid receptor (amino acids 88-153) .
  • the highly conserved amino acids of the DNA-binding domain of members of the superfamily are as follows:
  • X designates non-conserved amino acids within the DNA-binding domain; the amino acid residues denoted with an asterisk are residues that are almost universally conserved, but for which variations have been found in some identified hormone receptors; and the residues enclosed in parenthesis are optional residues (thus, the DNA-binding domain is a minimum of 66 amino acids in length, but can contain several additional residues) .
  • Exemplary members of the steroid/thyroid superfamily of receptors include steroid receptors such as glucocorticoid receptor (GR) , mineralocorticoid receptor (MR) , progesterone receptor (PR) , androgen receptor (AR) , vitamin D 3 receptor (VDR) , and the like; plus retinoi d receptors, such as various isoforms of the retinoic aci d receptor (e.g., RAR ⁇ , RAR/3, RAR ⁇ , and the like), plus various isoforms of the retinoid X receptor (e.g., RXR , RXR/?, RXR ⁇ , and the like) ; various isoforms of the thyroid hormone receptor (e.g., TR ⁇ , TR3, and the like); as well as other gene products which, by their structure an d properties, are considered to be members of the superfamily, as defined hereinabove.
  • GR glucocorticoid receptor
  • MR mineralocor
  • orphan receptors include various isoforms of HNF4 (see, for example, Sladek et al. , in Genes & Development 4:2353-2365 (1990)), the COUP family of receptors (e.g., COUP ⁇ or COUP,9; see, for example, Miyajima et al., in Nucleic Acids Research 16:11057-11074 (1988), Wang et al., in Nature 340:163-166 (1989), including the COUP-like receptors and COUP homologs, such as those described by Mlodzik et al., in Cell 60:211-224 (1990) and Ladias et al., in Science 251:561-565 (1991)), ultraspiracle (see, for example, Oro et al., in Nature 347:298-301 (1990)), various isoforms of peroxisome proliferator activated receptor (e.g., PPAR ⁇ , PPAR ⁇ or PPAR ⁇ ;
  • Presently preferred members of the steroid/thyroid superfamily of receptors contemplated for use in the practice of the present invention are selected from various isoforms of PPAR, VDR, CAR, LXR, FXR, NGFI-B, and the like.
  • the term "modulator” refers to a wide range of compounds and/or conditions which can, either directly or indirectly, exert an influence on the activation and/or repression of the receptor of interest (optionally associated with one or more of a heterodimerizing partner therefor, a co-activator and/or a hormone response element).
  • a ligand precursor i.e., a compound that can be converted into a ligand
  • a compound which converts a ligand precursor into an active ligand is also a modulator.
  • the precursor of a modulator i.e., a compound that can be converted into a modulator
  • a compound which converts a precursor into a modulator is also considered to be a modulator.
  • test compounds can be employed in the invention assays.
  • classes of compounds contemplated for use in the practice of the present invention include steroids, retinoids, prostaglandins, leukotrienes, thiazolidinediones, farnesoids, aminobenzoates, hydroxybenzoates, eicosanoids, cholesterol metabolites, fibrates, amino acids, sugars, nucleotides, fatty acids, lipids, serotonin, dopamine, catecholamines, acid azoles, and the like.
  • the plurality of test compounds employed in the invention assays can comprise a combinatorial library, wherein each individual test compound is one of an array of structurally related compounds.
  • contacting contemplated by the above-described assays can be carried out in solution, or in the solid phase. Where assays are conducted in solution, all components are dissolved or suspended in suitable media. The formation or disruption of complex caused by the presence of test compound can then be readily assayed in a variety of ways, as described in greater detail hereinbelow.
  • assays are conducted in solid phase, one or more of the components of the assay are immobilized on a suitable support, which is then exposed to the other components of the assay.
  • a suitable support which is then exposed to the other components of the assay.
  • the formation or disruption of complex caused by the presence of test compound can then be readily assayed in a variety of ways, as described in greater detail hereinbelow.
  • contacting contemplated by the invention assays can optionally be carried out in the presence of a heteromeric partner for the member of the superfamily, whereby the complex induced by the presence of test compound (or the complex disrupted by the presence of test compound) comprises said member and heteromeric partner therefor, optionally further containing a hormone response element and/or co-activator (or co-suppressor) therefor.
  • a heteromeric partner for use in the practice of the present invention is RXR.
  • contacting contemplated by the invention assays can optionally be carried out in the presence of a co-activator (or co-suppressor) for the member of the superfamily, whereby the complex induced by the presence of test compound (or the complex disrupted by the presence of test compound) comprises said member and said co-activator (or co-suppressor) , optionally further containing a heteromeric partner and/or hormone response element therefor.
  • a co-activator or co-suppressor
  • Co-activators contemplated for use in the practice of the present invention include SRC-1 (see, for example, Onate et al., in Science 270:1354-1357 (1995)), Tif (see, for example, LeDouarin et al., in EMBO Journal 14:2020-2033 (1995) and Baur et al., in EMBO Journal 15:110-124 (1996)), trip (see, for example, Lee et al.
  • Rip uo see, for example, Cavailles et al., in EMBO Journal 14:3741-3751 (1995)
  • ERAP see, for example, Halachmi et al., in Science 264:1455-1458 (1994)
  • N-CoR see, for example, Kurokawa et al., in Nature 377:451-454 (1995)
  • contacting contemplated by the invention assays can optionally be carried out in the presence of a hormone response element for the member of the superfamily, whereby the complex induced by the presence of test compound (or the complex disrupted by the presence of test compound) comprises said member and said hormone response element, optionally further containing a heteromeric partner and/or co- activator (or co-suppressor) therefor.
  • Hormone response elements contemplated for use in the practice of the present invention are well known and have been thoroughly described in the art. Such response elements can include direct repeat structures or inverted repeat structures based on well defined hexad half sites, as described in greater detail below. Exemplary hormone response elements are composed of at least one direct repeat of two or more half sites, separated by a spacer having in the range of 0 up to 6 nucleotides. The spacer nucleotides can be randomly selected from any one of A, C, G or T.
  • Each half site of response elements contemplated for use in the practice of the invention comprises the sequence:
  • R is selected from A or G;
  • M is selected from A or C; with the proviso that at least 4 nucleotides of said -RGBNNM- sequence are identical with the nucleotides at corresponding positions of the sequence -AGGTCA-.
  • Response elements employed in the practice of the present invention can optionally be preceded by N ⁇ , wherein x falls in the range of 0 up to 5.
  • Example methods include gel shift assays (see, for example, Forman et al., in Cell 81:687-693 (1995)), imrounological/affinity methods (see, for example, Yao et al., in Nature 366:476- 479 (1993)), surface plasmon resonance (see, for example, Fisher and Fivash in Curr. Opin. Biotechnol.
  • each of the steps contemplated herein i.e., contacting, assaying and identifying
  • steps contemplated herein can be substantially simultaneously carried out employing a format suitable for multiple exposures at the same time, e.g., employing a multi-well plate.
  • the large scale screening contemplated by the invention can be rendered even more time effective by automating the process.
  • test compounds e.g., various members of a combinatorial library
  • each well contains (or subsequently has added thereto) a receptor of interest, optionally in the presence of heteromeric partner therefor, a co-activator (or co-suppressor) and/or a hormone response element; each well can then be assayed to determine whether formation or disruption of complex is induced by test compound; and those compounds having such effect readily identified and selected for further testing as appropriate.
  • a co-activator or co-suppressor
  • Electrophoretic mobility shift assays were performed using proteins translated in a rabbit reticulocyte lysate system (TNT, Promega). Proteins (0.1-1 ⁇ l) were incubated with or without a specific modulator/ligand for 30 minutes at room temperature with 100,000 cpm of Klenow-labeled probesin 10 mM Tris pH 8, 150 mM KCl, 6% glycerol, 0.05% NP-40, 1 mM DTT, lOOng/ ⁇ l poly dI»dC and then electrophoresed through a 5% polyacrylamide gel in 0.5x TBE (45 mM Tris*base, 45 mM boric acid and 1 mM of EDTA. See Forman et al., in Cell 81:687-693 (1995).

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Endocrinology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne un procédé d'identification in vitro à large échelle de modulateurs de membres de la superfamille des récepteurs des stéroïdes ou thyroïdes. Le procédé de l'invention en permet une exécution rapide grâce au grand nombre de composés par module de test, ce qui facilite l'évaluation de grandes échantillothèques de composés en temps relativement court. Les modulateurs identifiés au moyens du procédé de l'invention sont capables d'activer une espèce récepteur en présence éventuellement d'au moins un partenaire d'hétérodimisation adapté, un co-activateur (ou d'un co-dépresseur), et/ou un élément de réponse hormonale. Mais de tels modulateurs sont également capables de bloquer l'activité d'une espèce récepteur en présence ou en l'absence éventuellement d'au moins un partenaire d'hétérodimisation adapté, d'un co-activateur (ou d'un co-dépresseur), et/ou d'un élément de réponse hormonale.
PCT/US1997/004315 1996-03-19 1997-03-19 Procede d'identification in vitro de modulateurs de membres de la superfamille des recepteurs des steroides ou thyroides WO1997035195A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU23324/97A AU2332497A (en) 1996-03-19 1997-03-19 (in vitro) methods for identifying modulators of members of the steroid/thyroid superfamily of receptors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61982896A 1996-03-19 1996-03-19
US08/619,828 1996-03-19

Publications (1)

Publication Number Publication Date
WO1997035195A1 true WO1997035195A1 (fr) 1997-09-25

Family

ID=24483475

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/004315 WO1997035195A1 (fr) 1996-03-19 1997-03-19 Procede d'identification in vitro de modulateurs de membres de la superfamille des recepteurs des steroides ou thyroides

Country Status (2)

Country Link
AU (1) AU2332497A (fr)
WO (1) WO1997035195A1 (fr)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062507A1 (fr) * 1998-06-02 1999-12-09 Arthromics Plc Composes capables d'interaction avec le recepteur d'hormone thyroidienne pour le traitement des maladies fibrosantes
WO1999064044A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Agents therapeutiques modulant les recepteurs 5-ht
WO1999064032A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Synthese combinatoire de banques de multiliaison
WO1999064031A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. AGONISTES DU RECEPTEUR β2-ADRENERGIQUE
WO1999064037A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Nouveaux agents therapeutiques modulant les processus enzymatiques
WO1999064046A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Agonistes polyvalents, agonistes partiels, agonistes inverses et antagonistes des recepteurs 5-ht¿3?
WO1999063994A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. INHIBITEURS MULTILIAISON DE HMG-CoA REDUCTASE
WO1999064045A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Agents therapeutiques agissant sur les transporteurs membranaires
WO1999064036A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Nouveaux agents therapeutiques pour structures macromoleculaires
WO2000057915A1 (fr) * 1999-03-26 2000-10-05 City Of Hope Procédé d'affectation du catabolisme du cholestérol au moyen d'un récepteur d'acide bilaire nucléaire
US6184256B1 (en) 1997-04-24 2001-02-06 INSTITUT NATIONAL DE LA SANTé DE LA RECHERCHE MéDICALE Methods and compositions for use in modulating expression of matrix metalloproteinase genes
US6420560B1 (en) 1999-06-07 2002-07-16 Theravance, Inc. H1—histamine receptor antagonists
US6548739B2 (en) 1999-06-18 2003-04-15 City Of Hope Method for activating peroxisome proliferator activated receptor-γ
US6562589B1 (en) 1997-06-17 2003-05-13 The United States Of America As Represented By The Department Of Health And Human Services AIB1, a novel steroid receptor co-activator
US6576793B1 (en) 1999-12-08 2003-06-10 Theravance, Inc. β2-adrenergic receptor agonists
US6586189B2 (en) 1999-06-18 2003-07-01 City Of Hope Screening method for PPAR-γ ligands
US6593497B1 (en) 1999-06-02 2003-07-15 Theravance, Inc. β2-adrenergic receptor agonists
US6683115B2 (en) 1999-06-02 2004-01-27 Theravance, Inc. β2-adrenergic receptor agonists
US6713651B1 (en) 1999-06-07 2004-03-30 Theravance, Inc. β2-adrenergic receptor agonists
EP1068529A4 (fr) * 1998-03-30 2004-08-04 Univ California Methodes et composes de modulation de la liaison d'un coactivateur a des recepteurs nucleaires
EP1473042A1 (fr) * 1999-03-26 2004-11-03 City of Hope Régulation du catabolisme du cholesterol au moyen d'un récepteur FXR et criblage de composés modulant l'activité des récepteurs FXR
US6939848B2 (en) 2000-08-09 2005-09-06 Yale University Crystals of the large ribosomal subunit
US6947844B2 (en) 2000-08-09 2005-09-20 Yale University Modulators of ribosomal function and identification thereof
US6947845B2 (en) 2001-08-03 2005-09-20 Yale University Method of identifying molecules that bind to the large ribosomal subunit
US6952650B2 (en) 2001-08-03 2005-10-04 Yale University Modulators of ribosomal function and identification thereof
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ENDOCRIN., August 1996, Vol. 137, No. 8, TAKASHITA et al., "Molecular Cloning and Properties of a Full-Length Putative Thyroid Hormone Receptor Coactivator", pages 3594-3597. *
GENE EXPRESSION, December 1996, Vol. 6, No. 3, ZHU et al., "Cloning and Identification of Mouse Steroid Receptor Coactivator-1 (mSRC-1), as a Coactivator of Peroxisome Proliferator-Activated Receptor-Gamma", pages 185-195. *
GENES & DEVELOPMENT, 1995, Vol. 9, PERLMAN et al., "A Novel Pathway for Vitamin A Signalling Mediated by RXR Heterodimerization with NGFI-B and NURR-1", pages 769-782. *
MOL. ENDOCRIN., December 1996, Vol. 10, No. 12, PETTY et al., "A TATA Binding Protein-Associated Factor Functions as a Co-Activator for Thyroid Receptors", pages 1632-1645. *

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6184256B1 (en) 1997-04-24 2001-02-06 INSTITUT NATIONAL DE LA SANTé DE LA RECHERCHE MéDICALE Methods and compositions for use in modulating expression of matrix metalloproteinase genes
US7232890B2 (en) 1997-06-17 2007-06-19 The United States Of America As Represented By The Department Of Health And Human Services AIB1, a novel steroid receptor co-activator
US6562589B1 (en) 1997-06-17 2003-05-13 The United States Of America As Represented By The Department Of Health And Human Services AIB1, a novel steroid receptor co-activator
US6965850B2 (en) 1998-03-30 2005-11-15 The Regents Of The University Of California Methods for modulating nuclear receptor coactivator binding
EP1068529A4 (fr) * 1998-03-30 2004-08-04 Univ California Methodes et composes de modulation de la liaison d'un coactivateur a des recepteurs nucleaires
US6414026B1 (en) 1998-06-02 2002-07-02 Arthromics Plc Compounds which interact with the thyroid hormone receptor for the treatment of fibrotic disease
WO1999062507A1 (fr) * 1998-06-02 1999-12-09 Arthromics Plc Composes capables d'interaction avec le recepteur d'hormone thyroidienne pour le traitement des maladies fibrosantes
US6348497B1 (en) 1998-06-02 2002-02-19 Arthromics Plc Compounds which interact with the thyroid hormone receptor for the treatment of fibrotic disease
US6362371B1 (en) 1998-06-08 2002-03-26 Advanced Medicine, Inc. β2- adrenergic receptor agonists
US6566509B1 (en) 1998-06-08 2003-05-20 Theravance, Inc. Multivalent macrolide antibiotics
WO1999064052A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Nouveaux antagonistes de recepteurs de leucotriene et leurs utilisations
WO1999064047A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Composes antiviraux
WO1999063983A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. AGENTS A LIAISONS MULTIPLES MODULANT LES RECEPTEURS PPARη ET RXR
WO1999064036A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Nouveaux agents therapeutiques pour structures macromoleculaires
WO1999064055A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Agonistes multivalents, agonistes partiels, agonistes inverses et antagonistes des recepteurs de 5ht¿4?
WO1999063999A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Antagonistes du recepteur h1 de l'histamine
WO1999064034A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. AGONISTES DU RECEPTEUR β2-ADRENERGIQUE
WO1999063930A3 (fr) * 1998-06-08 2000-01-27 Advanced Medicine Inc Nouveaux modulateurs des récepteurs de l'angiotensine et leurs utilisations
WO1999063932A3 (fr) * 1998-06-08 2000-02-03 Advanced Medicine Inc Agents de liaison multiple, modulant le transporteur de 5-ht
WO1999063944A3 (fr) * 1998-06-08 2000-02-10 Advanced Medicine Inc Nouveaux agents therapeutiques modulant les recepteurs des oestrogenes
WO1999063937A3 (fr) * 1998-06-08 2000-03-02 Advanced Medicine Inc Macrolides polyvalents
EP1019360A4 (fr) * 1998-06-08 2000-07-19 Advanced Medicine Inc AGONISTES DU RECEPTEUR $g(b)2-ADRENERGIQUE
WO1999064044A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Agents therapeutiques modulant les recepteurs 5-ht
WO1999064035A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. AGONISTES DU RECEPTEUR β2-ADRENERGIQUE
SG81994A1 (en) * 1998-06-08 2001-07-24 Advanced Medicine Inc Beta 2-adrenergic receptor agonists
WO1999064048A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Inhibiteurs de la transcriptase inverse du vih
US6355810B1 (en) 1998-06-08 2002-03-12 Advanced Medicine, Inc. Multibinding inhibitors of HMG-CoA reductase
WO1999063994A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. INHIBITEURS MULTILIAISON DE HMG-CoA REDUCTASE
WO1999064046A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Agonistes polyvalents, agonistes partiels, agonistes inverses et antagonistes des recepteurs 5-ht¿3?
WO1999064032A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Synthese combinatoire de banques de multiliaison
US6541669B1 (en) 1998-06-08 2003-04-01 Theravance, Inc. β2-adrenergic receptor agonists
SG108209A1 (en) * 1998-06-08 2005-01-28 Advanced Medicine Inc Combinatorial synthesis of multibinding libraries
WO1999064037A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Nouveaux agents therapeutiques modulant les processus enzymatiques
WO1999064045A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Agents therapeutiques agissant sur les transporteurs membranaires
SG106561A1 (en) * 1998-06-08 2004-10-29 Advanced Medicine Inc Therapeutic agents for macromolecular structures
SG106036A1 (en) * 1998-06-08 2004-09-30 Advanced Medicine Inc Novel therapeutic agents that modulate enzymatic processes
WO1999064031A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. AGONISTES DU RECEPTEUR β2-ADRENERGIQUE
EP1473042A1 (fr) * 1999-03-26 2004-11-03 City of Hope Régulation du catabolisme du cholesterol au moyen d'un récepteur FXR et criblage de composés modulant l'activité des récepteurs FXR
WO2000057915A1 (fr) * 1999-03-26 2000-10-05 City Of Hope Procédé d'affectation du catabolisme du cholestérol au moyen d'un récepteur d'acide bilaire nucléaire
US6593497B1 (en) 1999-06-02 2003-07-15 Theravance, Inc. β2-adrenergic receptor agonists
US6683115B2 (en) 1999-06-02 2004-01-27 Theravance, Inc. β2-adrenergic receptor agonists
US6420560B1 (en) 1999-06-07 2002-07-16 Theravance, Inc. H1—histamine receptor antagonists
US6713651B1 (en) 1999-06-07 2004-03-30 Theravance, Inc. β2-adrenergic receptor agonists
US6586189B2 (en) 1999-06-18 2003-07-01 City Of Hope Screening method for PPAR-γ ligands
US6548739B2 (en) 1999-06-18 2003-04-15 City Of Hope Method for activating peroxisome proliferator activated receptor-γ
US6576793B1 (en) 1999-12-08 2003-06-10 Theravance, Inc. β2-adrenergic receptor agonists
US7504486B2 (en) 2000-08-09 2009-03-17 Yale University Determination and uses of the atomic structures of ribosomes and ribosomal subunits and their ligand complexes
US6947844B2 (en) 2000-08-09 2005-09-20 Yale University Modulators of ribosomal function and identification thereof
US6939848B2 (en) 2000-08-09 2005-09-06 Yale University Crystals of the large ribosomal subunit
US6952650B2 (en) 2001-08-03 2005-10-04 Yale University Modulators of ribosomal function and identification thereof
US6947845B2 (en) 2001-08-03 2005-09-20 Yale University Method of identifying molecules that bind to the large ribosomal subunit
US7666849B2 (en) 2001-08-03 2010-02-23 Rib-X Pharmaceuticals, Inc. Ribosome structure and protein synthesis inhibitors
US8470990B2 (en) 2001-08-03 2013-06-25 Rib-X Pharmaceuticals, Inc. Ribosome structure and protein synthesis inhibitors
US8912150B2 (en) 2001-08-03 2014-12-16 Melinta Therapeutics, Inc. Ribosome structure and protein synthesis inhibitors
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7335753B2 (en) 2002-09-26 2008-02-26 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8841263B2 (en) 2004-02-27 2014-09-23 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same

Also Published As

Publication number Publication date
AU2332497A (en) 1997-10-10

Similar Documents

Publication Publication Date Title
WO1997035195A1 (fr) Procede d'identification in vitro de modulateurs de membres de la superfamille des recepteurs des steroides ou thyroides
Klinge et al. Binding of type II nuclear receptors and estrogen receptor to full and half-site estrogen response elements in vitro
Lee et al. The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression
Hu et al. Transcription activation by the ecdysone receptor (EcR/USP): identification of activation functions
Harding et al. Transcriptional activation and repression by RORα, an orphan nuclear receptor required for cerebellar development
Mathur et al. PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors
Valley et al. Differential regulation of estrogen-inducible proteolysis and transcription by the estrogen receptor α N terminus
Sun et al. Estrogen-induced retinoic acid receptor α1 gene expression: role of estrogen receptor-Sp1 complex
Klinge et al. Chicken ovalbumin upstream promoter-transcription factor interacts with estrogen receptor, binds to estrogen response elements and half-sites, and inhibits estrogen-induced gene expression
Boonyaratanakornkit et al. High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells
Rayasam et al. Ligand-specific dynamics of the progesterone receptor in living cells and during chromatin remodeling in vitro
Hong et al. Signaling by tyrosine kinases negatively regulates the interaction between transcription factors and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor
Steffensen et al. Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ‐F1 homologue
JP2002330759A (ja) 遺伝子発現を使用して生産物を同定する方法
Sugiyama et al. Transcription activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI): definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene
EP0743520A2 (fr) Utilisations nouvelles des structures de GAL4-récepteur
Osburn et al. Ligand-dependent degradation of retinoid X receptors does not require transcriptional activity or coactivator interactions
Kim et al. Molecular cloning of xSRC-3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2
Le Douarin et al. TIF1α: a possible link between KRAB zinc finger proteins and nuclear receptors
Avram et al. Heterodimeric interactions between chicken ovalbumin upstream promoter-transcription factor family members ARP1 and ear2
Butt et al. Human nuclear receptor heterodimers: opportunities for detecting targets of transcriptional regulation using yeast
Dilworth et al. Ligand-dependent activation of transcription in vitro by retinoic acid receptor α/retinoid X receptor α heterodimers that mimics transactivation by retinoids in vivo
WO2006055786A2 (fr) Outils permettant l'identification de ligands pour recepteurs nucleaires hormonaux
DE60317330T2 (de) Systeme und verfahren zum nachweis der funktion nukleärer rezeptoren unter verwendung von reporterenzymmutanten komplementierungen
Sanguedolce et al. The promoter context is a decisive factor in establishing selective responsiveness to nuclear class II receptors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97533625

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载