Selective androgen receptor modulators and methods for their identification, design and use

Abstract

Selective androgen receptor modulators (SARMs) having antagonist activity in hormone-dependent tumors while exhibiting no activity or agonist activity against other nontumor tissues containing the androgen receptor as well as methods for identifying, designing and using SARMs are provided.

1 - 12 . (canceled)  
     
     
         13 . A molecule or molecular complex comprising all or any part of the ligand binding site defined by structure coordinates of AR-LBD amino acids V685, L700, L701, S702, S703, L704, N705, E706, L707, G708, E709, Q711, A735, 1737, Q738, Y739, S740, W741, M742, G743, L744, M745, V746, F747, A748, M749, G750, R752, Y763, F764, A765, L768, F770, M780, M787, 1869, L873, H874, F876, T877, F878, M894, M895, A896, E897, I898, I899, S900, V901, Q902, V903, P904, K905, I906 and L907 according to Table A, or a mutant or homologue of said molecule or molecular complex.  
     
     
         14 . The molecule or molecular complex of  claim 13  wherein said mutant or homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said AR-LBD amino acids of not more than 1.5 Angstroms or 30% sequence identity with said AR-LBD amino acids.  
     
     
         15 . The molecule or molecular complex of  claim 13  comprising all or any part of the ligand binding site defined by structure coordinates of AR-LBD amino acids N705, W741, Q711, R752, F764, T877, M895 and I898 according to Table A, or a mutant or homologue of said molecule or molecular complex.  
     
     
         16 . The molecule or molecular complex of  claim 15  wherein said mutant or homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said AR-LBD amino acids of not more than 1.5 Angstroms or 30% sequence identity with said AR-LBD amino acids.  
     
     
         17 - 19 . (canceled)  
     
     
         20 . A binding site in AR-LBD for an AR modulator in which a portion of said ligand is in van der Walls contact or hydrogen bonding contact with any portion or all of residues V685, L700, L701, S702, S703, L704, N705, E706, L707, G708, E709, Q711, A735, I737, Q738, Y739, S740, W741, M742, G743, L744, M745, V746, F747, A748, M749, G750, R752, Y763, F764, A765, L768, F770, M780, M787, I869, L873, H874, F876, T877, F878, L880, L881, V889, F891, P892, E893, M894, M895, A896, E897, I898, I899, S900, V901, Q902, V903, P904, K905, I906 or L907 of AR-LBD according to Table A.  
     
     
         21 . The binding site according to  claim 20  wherein the AR-LBD is a homologue or mutant with 25%-95% identity to residues V685, L700, L701, S702, S703, L704, N705, E706, L707, G708, E709, Q711, A735, I737, Q738, Y739, S740, W741, M742, G743, L744, M745, V746, F747, A748, M749, G750, R752, Y763, F764, A765, L768, F770, M780, M787, I869, L873, H874, F876, T877, F878, L880, L881, V889, F891, P892, E893, M894, M895, A896, E897, I898, I899, S900, V901, Q902, V903, P904, K905, I906, or L907 of AR-LBD according to Table A.  
     
     
         22 . A computational method of designing an androgen receptor synthetic ligand comprising: 
 a. using a three dimensional model of a crystallized protein comprising an AR-LBD/AR-LBD ligand complex to determine at least one interacting amino acid of the AR-LBD that interacts with at least one first chemical moiety of the AR-LBD ligand; and    b. selecting at least one chemical modification of said first chemical moiety to produce a second chemical moiety with a structure that either decreases or increases an interaction between said interacting amino acid and said second chemical moiety compared to said interaction between said interacting amino acid and said first chemical moiety.    
     
     
         23 . A method for identifying a compound that modulates androgen receptor activity, the method comprising any combination of steps of: 
 a. modeling test compounds that fit spatially into the AR-LBD as defined by structure coordinates according to Table A, or using a three-dimensional structural model of AR-LBD, mutant AR-LBD or AR-LBD homologue or portion thereof;    b. using said structure coordinates or ligand binding site as set forth in  claim 20  to identify structural and chemical features;    c. employing identified structural or chemical features to design or select compounds as potential SARMs;    d. employing the three-dimensional structural model or the ligand binding site to design or select compounds as potential SARMs;    e. synthesizing the potential SARMs;    f. screening the potential SARMs in an assay characterized by binding of a test compound to the AR-LBD; and    g. modifying or replacing one or more amino acids from AR-LBD selected from the group consisting of V685, L700, L701, S702, S703, L704, N705, E706, L707, G708, E709, Q711, A735, I737, Q738, Y739, S740, W741, M742, G743, L744, M745, V746, F747, A748, M749, G750, R752, Y763, F764, A765, L768, F770, M780, M787, 1869, L873, H874, F876, T877, F878, L880, L881, V889, F891, P892, E893, M894, M895, A896, E897, I898, I899, S900, V901, Q902, V903, P904, K905, I906 or L907 of AR-LBD according to Table A.    
     
     
         24 . (canceled)