WO2002002488A3 - Methods and compounds for modulating nuclear receptor coactivator binding - Google Patents

Methods and compounds for modulating nuclear receptor coactivator binding Download PDF

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Publication number
WO2002002488A3
WO2002002488A3 PCT/US2001/020969 US0120969W WO0202488A3 WO 2002002488 A3 WO2002002488 A3 WO 2002002488A3 US 0120969 W US0120969 W US 0120969W WO 0202488 A3 WO0202488 A3 WO 0202488A3
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WO
WIPO (PCT)
Prior art keywords
coactivator binding
methods
nuclear receptor
compounds
receptor coactivator
Prior art date
Application number
PCT/US2001/020969
Other languages
French (fr)
Other versions
WO2002002488A2 (en
WO2002002488A9 (en
Inventor
Rodney K Guy
John D Baxter
Beatrice Darimont
Weijun Feng
Robert J Fletterick
Peter J Kushner
Richard L Wagner
Brian L West
Keith R Yamamoto
Timothy R Geistlinger
James R Arnold
Irwin D Kuntz
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Univ California
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.)
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Publication date
Application filed by Univ California filed Critical Univ California
Priority to EP01950770A priority Critical patent/EP1297175A4/en
Priority to CA002415103A priority patent/CA2415103A1/en
Publication of WO2002002488A2 publication Critical patent/WO2002002488A2/en
Publication of WO2002002488A3 publication Critical patent/WO2002002488A3/en
Publication of WO2002002488A9 publication Critical patent/WO2002002488A9/en

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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • G16B20/30—Detection of binding sites or motifs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/08—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6875—Nucleoproteins
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G16B15/30—Drug targeting using structural data; Docking or binding prediction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Evolutionary Biology (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Medical Informatics (AREA)
  • Theoretical Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to methods and agonist/antagonist compounds for modulating nuclear receptor coactivator binding. The invention includes a method for identifying residues comprising a coactivator binding site for a nuclear receptor of interest. Also included is a method of identifying agonists and/or antagonists that bind to a coactivator binding site of a nuclear receptor of interest. Agonists and antagonists of coactivator binding to nuclear receptors also are provided. The invention is exemplified by identification and manipulation of the coactivator binding site of the thyroid receptor (TR), and compounds that bind to this sites. The methods can be applied to other nuclear receptors including RAR, RXR, PPAR, VDR, ER, GR, PR, MR, and AR.
PCT/US2001/020969 2000-06-30 2001-06-29 Methods and compounds for modulating nuclear receptor coactivator binding WO2002002488A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP01950770A EP1297175A4 (en) 2000-06-30 2001-06-29 Methods and compounds for modulating nuclear receptor coactivator binding
CA002415103A CA2415103A1 (en) 2000-06-30 2001-06-29 Methods and compounds for modulating nuclear receptor coactivator binding

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60936100A 2000-06-30 2000-06-30
US09/609,361 2000-06-30

Publications (3)

Publication Number Publication Date
WO2002002488A2 WO2002002488A2 (en) 2002-01-10
WO2002002488A3 true WO2002002488A3 (en) 2002-04-18
WO2002002488A9 WO2002002488A9 (en) 2003-09-12

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/020969 WO2002002488A2 (en) 2000-06-30 2001-06-29 Methods and compounds for modulating nuclear receptor coactivator binding

Country Status (3)

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EP (1) EP1297175A4 (en)
CA (1) CA2415103A1 (en)
WO (1) WO2002002488A2 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003230943A1 (en) * 2002-04-15 2003-11-03 The Regents Of The University Of California Method for obtaining the binding affinities of a peptide library to a protein
WO2005085865A2 (en) * 2004-03-09 2005-09-15 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with thyroid hormone receptor beta (thrb)
US7973135B2 (en) 2006-07-12 2011-07-05 Oncotx, Inc. Compositions and methods for targeting cancer-specific transcription complexes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0640592A1 (en) * 1993-07-29 1995-03-01 American Cyanamid Company N-acylated tricyclic azaheterorings useful as vasopressin antagonists
WO1996005185A1 (en) * 1994-08-16 1996-02-22 Mitsubishi Chemical Corporation Novel alkylamino derivatives as sigma 2 selective ligands
US5684711A (en) * 1994-09-16 1997-11-04 3-Dimensional Pharmaceuticals, Inc. System, method, and computer program for at least partially automatically generating chemical compounds having desired properties

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101681B1 (en) * 1997-11-21 2006-09-05 Amgen, Inc. Nuclear hormone receptor drug screens
CA2324060A1 (en) * 1998-03-30 1999-10-07 The Regents Of The University Of California Methods and compounds for modulating nuclear receptor activity
US6965850B2 (en) * 1998-03-30 2005-11-15 The Regents Of The University Of California Methods for modulating nuclear receptor coactivator binding

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0640592A1 (en) * 1993-07-29 1995-03-01 American Cyanamid Company N-acylated tricyclic azaheterorings useful as vasopressin antagonists
WO1996005185A1 (en) * 1994-08-16 1996-02-22 Mitsubishi Chemical Corporation Novel alkylamino derivatives as sigma 2 selective ligands
US5684711A (en) * 1994-09-16 1997-11-04 3-Dimensional Pharmaceuticals, Inc. System, method, and computer program for at least partially automatically generating chemical compounds having desired properties

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
EDWARDS ET AL.: "New non-steriodal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino (3,2-g)quinolinone", BIOORG. MED. CHEM. LETT., vol. 8, 7 April 1998 (1998-04-07), pages 745 - 750, XP004136958 *
FENG ET AL.: "Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors", SCIENCE, vol. 280, no. 5370, 12 June 1998 (1998-06-12), pages 1747 - 1749, XP002906505 *
GORDON ET AL.: "Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies and future directions", J. MED. CHEM., vol. 37, no. 10, 13 May 1994 (1994-05-13), pages 1385 - 1401, XP002927721 *
HONG ET AL.: "An additional region of coactivator GRIP1 required for interaction with the hormone-binding domains of a subset of nuclear receptors", J. BIOL. CHEM., vol. 274, no. 6, 5 February 1999 (1999-02-05), pages 3496 - 3502, XP002906501 *
MA ET AL.: "Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins", MOL. CELL. BIOL., vol. 19, no. 9, September 1999 (1999-09-01), pages 6164 - 6173, XP002906504 *
MUEGGE ET AL.: "Evaluation of PMF scoring in docking weak ligands to the FK506 binding protein", J. MED. CHEM., vol. 42, no. 14, 15 July 1999 (1999-07-15), pages 2498 - 2503, XP002906506 *
NOLTE ET AL.: "Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma", NATURE, vol. 395, 10 September 1998 (1998-09-10), pages 137 - 143, XP002906503 *
SCHMIDT ET AL.: "Multiple receptor interaction domains of GRIP1 function in synergy", NUC. ACID RES., vol. 26, no. 5, 1 March 1998 (1998-03-01), pages 1191 - 1197, XP002906502 *

Also Published As

Publication number Publication date
WO2002002488A2 (en) 2002-01-10
CA2415103A1 (en) 2002-01-10
WO2002002488A9 (en) 2003-09-12
EP1297175A4 (en) 2005-02-02
EP1297175A2 (en) 2003-04-02

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