Inhibitors for androgen antagonist refractory prostate cancer
First Claim
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1. A method of identifying a compound that modulates nuclear receptor activity, the method comprising:
- modeling a test compound that fits spatially into an atomic structural model of the androgen receptor coactivator binding site or portion thereof, wherein said atomic structural model comprises atomic coordinates of an androgen receptor coactivator binding site and a molecule bound to the coactivator binding site; and
screening said test compound in an assay characterized by binding of the test compound to the coactivator binding site of a nuclear receptor, thereby identifying a test compound that modulates nuclear receptor activity.
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Abstract
The present invention relates to methods and antagonist compounds for modulating androgen receptor activity. The invention includes a method for identifying molecules that bind to a coactivator binding site of a receptor in the androgen receptor family. Also included is a cocrystal of an androgen receptor ligand binding domain complexed with a ligand and a coactivator. The invention further includes a method for inhibiting androgen receptor activity in a mammal, thereby facilitating treatment of diseases such as prostate cancer.
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Citations
117 Claims
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1. A method of identifying a compound that modulates nuclear receptor activity, the method comprising:
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modeling a test compound that fits spatially into an atomic structural model of the androgen receptor coactivator binding site or portion thereof, wherein said atomic structural model comprises atomic coordinates of an androgen receptor coactivator binding site and a molecule bound to the coactivator binding site; and
screening said test compound in an assay characterized by binding of the test compound to the coactivator binding site of a nuclear receptor, thereby identifying a test compound that modulates nuclear receptor activity. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)
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27. A method of identifying a compound that modulates nuclear receptor activity, the method comprising:
screening a test compound in an assay characterized by binding of a test compound to the coactivator binding site of a nuclear receptor, wherein the test compound has been modeled by spatially fitting an atomic model of the test compound into an atomic structural model of a portion of the androgen receptor coactivator binding site, wherein said atomic structural model comprises atomic coordinates of amino acid residues of the androgen receptor coactivator binding site and a molecule bound to the coactivator binding site, thereby identifying a test compound that modulates nuclear receptor activity. - View Dependent Claims (28, 29, 30, 31, 32, 33, 34)
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35. A method of identifying an antagonist of coactivator binding to a nuclear receptor, the method comprising:
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modeling a test compound which fits spatially into an atomic structural model of the androgen receptor coactivator binding site wherein the atomic structural model comprises atomic coordinates of amino acid residues of human androgen receptor coactivator binding site and a molecule bound to the coactivator binding site; and
screening said test compound in an assay for nuclear receptor activity, thereby identifying a compound which decreases the activity of the nuclear receptor by binding the coactivator binding site of said nuclear receptor. - View Dependent Claims (36, 37, 38, 39, 40, 41, 42, 43, 44, 45)
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46. A method of identifying a compound that modulates androgen receptor activity, said method comprising:
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modeling a test compound that fits spatially into an atomic structural model of an androgen receptor coactivator binding site, wherein said atomic structural model comprises atomic coordinates of amino acid residues of the androgen receptor coactivator binding site, and a molecule bound to the coactivator binding site; and
screening said test compound in an assay characterized by binding of the test compound to the androgen receptor coactivator binding site, thereby identifying a compound that modulates coactivator binding to the androgen receptor. - View Dependent Claims (47, 48, 49, 50, 51, 52, 53, 54, 55)
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56. A method of identifying an antagonist of coactivator binding to an androgen receptor, said method comprising:
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modeling a test compound that fits spatially into the androgen receptor coactivator binding site using an atomic structural model of the androgen receptor coactivator binding site, wherein said atomic structural model comprises coordinates of the androgen receptor coactivator binding site, and coordinates of a coactivator bound to said coactivator binding site, and screening said test compound in an assay characterized by binding of a test compound to the nuclear receptor coactivator binding site, thereby identifying a compound that inhibits coactivator binding to the androgen receptor. - View Dependent Claims (57, 58, 59, 60, 61, 62, 63, 64, 65)
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66. A computational method of designing an inhibitor of androgen receptor coactivator binding, comprising:
- fitting an atomic model of the compound into an atomic structural model of the coactivator binding site of the androgen receptor, wherein said compound consists of a first moiety that fits into a first cleft on the coactivator binding site and contacts at least one residue selected from the group consisting of Leu 712, Val 716, Met 734, Gln 738, Met 894, and Ile 898, and a second moiety that fits into a second cleft on the coactivator binding site, and contacts at least one residue selected from the group consisting of Val 716, Lys 720, Phe 725, Val 730, Gln 733, Ile 737, wherein said first moiety and said second moiety are joined by a linking group.
- View Dependent Claims (67, 68, 69, 70, 71)
- 72. A method of modulating androgen receptor activity in a mammal by administering to a mammal in need thereof a sufficient amount of a compound that fits spatially and preferentially into a coactivator binding site of the androgen receptor, wherein said compound is designed by a computational method that involves fitting an atomic model of the compound into an atomic structural model of the coactivator binding site of the androgen receptor, and wherein said compound consists of a first moiety that fits into a first cleft on the coactivator binding site and contacts at least one residue selected from the group consisting of Leu 712, Val 716, Met 734, Gln 738, Met 894, and Ile 898, and a second moiety that fits into a second cleft on the coactivator binding site, and contacts at least one residue selected from the group consisting of Val 716, Lys 720, Phe 725, Val 730, Gln 733, Ile 737, wherein said first moiety and said second moiety are joined by a linking group.
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76. A method of inhibiting the binding of a coactivator to an androgen receptor, said method comprising:
contacting a molecule with a coactivator binding site on the androgen receptor, wherein the molecule fits spatially into the coactivator binding site, and wherein the molecule binds more strongly to the receptor than does the coactivator. - View Dependent Claims (77, 78, 79, 80, 81)
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82. A method of modulating the activity of an androgen receptor, said method comprising:
contacting a molecule with a coactivator binding site on the androgen receptor, wherein the molecule fits spatially into the coactivator binding site, and wherein the molecule has been designed by modeling at least one test compound into an atomic structural model of the coactivator binding site of the androgen receptor, wherein said atomic structural model comprises atomic coordinates of amino acid residues of the androgen receptor coactivator binding site and a second molecule bound to the coactivator binding site. - View Dependent Claims (83, 84)
- 85. A method of modulating androgen receptor activity in a mammal by administering to a mammal in need thereof a sufficient amount of a compound that fits spatially and preferentially into a coactivator binding site of the androgen receptor, wherein said compound is designed by fitting an atomic model of the compound into an atomic structural model of the coactivator binding site of the androgen receptor, wherein said atomic structural model comprises atomic coordinates of amino acid residues of the androgen receptor coactivator binding site and a second molecule bound to the coactivator binding site.
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88. A machine-readable data storage medium encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of causing a graphical three-dimensional representation of a molecular complex to be displayed, comprising:
- at least a portion of an androgen receptor ligand binding domain, including an androgen receptor coactivator binding site;
a molecule bound to the androgen receptor coactivator binding site; and
a ligand bound to the ligand binding domain. - View Dependent Claims (89, 90, 91, 92, 93)
- at least a portion of an androgen receptor ligand binding domain, including an androgen receptor coactivator binding site;
- 94. Use of a machine-readable data storage medium, comprising machine readable data, in conjunction with a machine programmed with instructions for using said data, for identifying a molecule that modulates coactivator binding to an androgen receptor, wherein the computer displays a graphical three-dimensional representation of a complex of the molecule bound to a coactivator binding site of the androgen receptor, and wherein the data comprises structure coordinates in any one of Table 1 (A) and (B), and Table 2 (A)-(H), found respectively in the files identified as Table1_ARLBD_DHT_CDP.txt and Table2_ARLBD_DHT_CRP.txt, presented on CD-R herewith.
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96. A cocrystal comprising:
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a portion of an androgen receptor ligand binding domain;
a ligand bound to the ligand binding domain of the receptor; and
a coactivator bound to a coactivator binding site of the receptor. - View Dependent Claims (97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107)
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108. A cocrystal consisting of:
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an androgen receptor ligand binding domain;
a ligand bound to the ligand binding domain of the receptor;
a coactivator bound to a coactivator binding site of the receptor; and
crystallographically bound water.
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109. An isolated and purified protein complex comprising:
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a portion of an androgen receptor ligand binding domain;
a ligand bound to the ligand binding domain of the receptor; and
a coactivator bound to a coactivator binding site of the receptor. - View Dependent Claims (110, 111)
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112. An isolated and purified protein complex consisting of:
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an androgen receptor ligand binding domain;
a ligand bound to the ligand binding domain of the receptor;
a coactivator bound to a coactivator binding site of the receptor; and
at least one molecule of solvent bound thereto.
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113. An isolated and purified polypeptide consisting of a portion of the human androgen receptor starting at amino acid residue 669 and ending at amino acid residue 918, as set forth in SEQ ID NO:
- 29, bound to a ligand, and bound to a coactivator.
- View Dependent Claims (114, 115)
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116. A compound of formula:
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117. A method of treating prostate cancer by administering a pharmaceutical composition comprising a compound of formula:
Specification