                         SEQUENCE LISTING

<110>  The Trustees of the University of Pennsylvania
       Penning, Trevor
       Adeniji, Adegoke
       Byrns, Michael
       Winkler, Jeffrey
       Twenter, Barry
 
<120>  Bifunctional AKR1C3 Inhibitors/Androgen Receptor Modulators and 
       Methods of Use Thereof

<130>  46483-6005-00-W0.601382

<150>  US 61/475,091
<151>  2011-04-13

<160>  6     

<170>  PatentIn version 3.5

<210>  1
<211>  323
<212>  PRT
<213>  Homo sapiens

<400>  1

Met Asp Ser Lys Tyr Gln Cys Val Lys Leu Asn Asp Gly His Phe Met 
1               5                   10                  15      


Pro Val Leu Gly Phe Gly Thr Tyr Ala Pro Ala Glu Val Pro Lys Ser 
            20                  25                  30          


Lys Ala Leu Glu Ala Thr Lys Leu Ala Ile Glu Ala Gly Phe Arg His 
        35                  40                  45              


Ile Asp Ser Ala His Leu Tyr Asn Asn Glu Glu Gln Val Gly Leu Ala 
    50                  55                  60                  


Ile Arg Ser Lys Ile Ala Asp Gly Ser Val Lys Arg Glu Asp Ile Phe 
65                  70                  75                  80  


Tyr Thr Ser Lys Leu Trp Cys Asn Ser His Arg Pro Glu Leu Val Arg 
                85                  90                  95      


Pro Ala Leu Glu Arg Ser Leu Lys Asn Leu Gln Leu Asp Tyr Val Asp 
            100                 105                 110         


Leu Tyr Leu Ile His Phe Pro Val Ser Val Lys Pro Gly Glu Glu Val 
        115                 120                 125             


Ile Pro Lys Asp Glu Asn Gly Lys Ile Leu Phe Asp Thr Val Asp Leu 
    130                 135                 140                 


Cys Ala Thr Trp Glu Ala Val Glu Lys Cys Lys Asp Ala Gly Leu Ala 
145                 150                 155                 160 


Lys Ser Ile Gly Val Ser Asn Phe Asn Arg Arg Gln Leu Glu Met Ile 
                165                 170                 175     


Leu Asn Lys Pro Gly Leu Lys Tyr Lys Pro Val Cys Asn Gln Val Glu 
            180                 185                 190         


Cys His Pro Tyr Phe Asn Gln Arg Lys Leu Leu Asp Phe Cys Lys Ser 
        195                 200                 205             


Lys Asp Ile Val Leu Val Ala Tyr Ser Ala Leu Gly Ser His Arg Glu 
    210                 215                 220                 


Glu Pro Trp Val Asp Pro Asn Ser Pro Val Leu Leu Glu Asp Pro Val 
225                 230                 235                 240 


Leu Cys Ala Leu Ala Lys Lys His Lys Arg Thr Pro Ala Leu Ile Ala 
                245                 250                 255     


Leu Arg Tyr Gln Leu Gln Arg Gly Val Val Val Leu Ala Lys Ser Tyr 
            260                 265                 270         


Asn Glu Gln Arg Ile Arg Gln Asn Val Gln Val Phe Glu Phe Gln Leu 
        275                 280                 285             


Thr Ser Glu Glu Met Lys Ala Ile Asp Gly Leu Asn Arg Asn Val Arg 
    290                 295                 300                 


Tyr Leu Thr Leu Asp Ile Phe Ala Gly Pro Pro Asn Tyr Pro Phe Ser 
305                 310                 315                 320 


Asp Glu Tyr 
            


<210>  2
<211>  323
<212>  PRT
<213>  Homo sapiens

<400>  2

Met Asp Ser Lys Tyr Gln Cys Val Lys Leu Asn Asp Gly His Phe Met 
1               5                   10                  15      


Pro Val Leu Gly Phe Gly Thr Tyr Ala Pro Ala Glu Val Pro Lys Ser 
            20                  25                  30          


Lys Ala Leu Glu Ala Val Lys Leu Ala Ile Glu Ala Gly Phe His His 
        35                  40                  45              


Ile Asp Ser Ala His Val Tyr Asn Asn Glu Glu Gln Val Gly Leu Ala 
    50                  55                  60                  


Ile Arg Ser Lys Ile Ala Asp Gly Ser Val Lys Arg Glu Asp Ile Phe 
65                  70                  75                  80  


Tyr Thr Ser Lys Leu Trp Ser Asn Ser His Arg Pro Glu Leu Val Arg 
                85                  90                  95      


Pro Ala Leu Glu Arg Ser Leu Lys Asn Leu Gln Leu Asp Tyr Val Asp 
            100                 105                 110         


Leu Tyr Leu Ile His Phe Pro Val Ser Val Lys Pro Gly Glu Glu Val 
        115                 120                 125             


Ile Pro Lys Asp Glu Asn Gly Lys Ile Leu Phe Asp Thr Val Asp Leu 
    130                 135                 140                 


Cys Ala Thr Trp Glu Ala Met Glu Lys Cys Lys Asp Ala Gly Leu Ala 
145                 150                 155                 160 


Lys Ser Ile Gly Val Ser Asn Phe Asn His Arg Leu Leu Glu Met Ile 
                165                 170                 175     


Leu Asn Lys Pro Gly Leu Lys Tyr Lys Pro Val Cys Asn Gln Val Glu 
            180                 185                 190         


Cys His Pro Tyr Phe Asn Gln Arg Lys Leu Leu Asp Phe Cys Lys Ser 
        195                 200                 205             


Lys Asp Ile Val Leu Val Ala Tyr Ser Ala Leu Gly Ser His Arg Glu 
    210                 215                 220                 


Glu Pro Trp Val Asp Pro Asn Ser Pro Val Leu Leu Glu Asp Pro Val 
225                 230                 235                 240 


Leu Cys Ala Leu Ala Lys Lys His Lys Arg Thr Pro Ala Leu Ile Ala 
                245                 250                 255     


Leu Arg Tyr Gln Leu Gln Arg Gly Val Val Val Leu Ala Lys Ser Tyr 
            260                 265                 270         


Asn Glu Gln Arg Ile Arg Gln Asn Val Gln Val Phe Glu Phe Gln Leu 
        275                 280                 285             


Thr Ser Glu Glu Met Lys Ala Ile Asp Gly Leu Asn Arg Asn Val Arg 
    290                 295                 300                 


Tyr Leu Thr Leu Asp Ile Phe Ala Gly Pro Pro Asn Tyr Pro Phe Ser 
305                 310                 315                 320 


Asp Glu Tyr 
            


<210>  3
<211>  323
<212>  PRT
<213>  Homo sapiens

<400>  3

Met Asp Ser Lys His Gln Cys Val Lys Leu Asn Asp Gly His Phe Met 
1               5                   10                  15      


Pro Val Leu Gly Phe Gly Thr Tyr Ala Pro Pro Glu Val Pro Arg Ser 
            20                  25                  30          


Lys Ala Leu Glu Val Thr Lys Leu Ala Ile Glu Ala Gly Phe Arg His 
        35                  40                  45              


Ile Asp Ser Ala His Leu Tyr Asn Asn Glu Glu Gln Val Gly Leu Ala 
    50                  55                  60                  


Ile Arg Ser Lys Ile Ala Asp Gly Ser Val Lys Arg Glu Asp Ile Phe 
65                  70                  75                  80  


Tyr Thr Ser Lys Leu Trp Ser Thr Phe His Arg Pro Glu Leu Val Arg 
                85                  90                  95      


Pro Ala Leu Glu Asn Ser Leu Lys Lys Ala Gln Leu Asp Tyr Val Asp 
            100                 105                 110         


Leu Tyr Leu Ile His Ser Pro Met Ser Leu Lys Pro Gly Glu Glu Leu 
        115                 120                 125             


Ser Pro Thr Asp Glu Asn Gly Lys Val Ile Phe Asp Ile Val Asp Leu 
    130                 135                 140                 


Cys Thr Thr Trp Glu Ala Met Glu Lys Cys Lys Asp Ala Gly Leu Ala 
145                 150                 155                 160 


Lys Ser Ile Gly Val Ser Asn Phe Asn Arg Arg Gln Leu Glu Met Ile 
                165                 170                 175     


Leu Asn Lys Pro Gly Leu Lys Tyr Lys Pro Val Cys Asn Gln Val Glu 
            180                 185                 190         


Cys His Pro Tyr Phe Asn Arg Ser Lys Leu Leu Asp Phe Cys Lys Ser 
        195                 200                 205             


Lys Asp Ile Val Leu Val Ala Tyr Ser Ala Leu Gly Ser Gln Arg Asp 
    210                 215                 220                 


Lys Arg Trp Val Asp Pro Asn Ser Pro Val Leu Leu Glu Asp Pro Val 
225                 230                 235                 240 


Leu Cys Ala Leu Ala Lys Lys His Lys Arg Thr Pro Ala Leu Ile Ala 
                245                 250                 255     


Leu Arg Tyr Gln Leu Gln Arg Gly Val Val Val Leu Ala Lys Ser Tyr 
            260                 265                 270         


Asn Glu Gln Arg Ile Arg Gln Asn Val Gln Val Phe Glu Phe Gln Leu 
        275                 280                 285             


Thr Ala Glu Asp Met Lys Ala Ile Asp Gly Leu Asp Arg Asn Leu His 
    290                 295                 300                 


Tyr Phe Asn Ser Asp Ser Phe Ala Ser His Pro Asn Tyr Pro Tyr Ser 
305                 310                 315                 320 


Asp Glu Tyr 
            


<210>  4
<211>  323
<212>  PRT
<213>  Homo sapiens

<400>  4

Met Asp Pro Lys Tyr Gln Arg Val Glu Leu Asn Asp Gly His Phe Met 
1               5                   10                  15      


Pro Val Leu Gly Phe Gly Thr Tyr Ala Pro Pro Glu Val Pro Arg Asn 
            20                  25                  30          


Arg Ala Val Glu Val Thr Lys Leu Ala Ile Glu Ala Gly Phe Arg His 
        35                  40                  45              


Ile Asp Ser Ala Tyr Leu Tyr Asn Asn Glu Glu Gln Val Gly Leu Ala 
    50                  55                  60                  


Ile Arg Ser Lys Ile Ala Asp Gly Ser Val Lys Arg Glu Asp Ile Phe 
65                  70                  75                  80  


Tyr Thr Ser Lys Leu Trp Cys Thr Phe Phe Gln Pro Gln Met Val Gln 
                85                  90                  95      


Pro Ala Leu Glu Ser Ser Leu Lys Lys Leu Gln Leu Asp Tyr Val Asp 
            100                 105                 110         


Leu Tyr Leu Leu His Phe Pro Met Ala Leu Lys Pro Gly Glu Thr Pro 
        115                 120                 125             


Leu Pro Lys Asp Glu Asn Gly Lys Val Ile Phe Asp Thr Val Asp Leu 
    130                 135                 140                 


Ser Ala Thr Trp Glu Val Met Glu Lys Cys Lys Asp Ala Gly Leu Ala 
145                 150                 155                 160 


Lys Ser Ile Gly Val Ser Asn Phe Asn Cys Arg Gln Leu Glu Met Ile 
                165                 170                 175     


Leu Asn Lys Pro Gly Leu Lys Tyr Lys Pro Val Cys Asn Gln Val Glu 
            180                 185                 190         


Cys His Pro Tyr Leu Asn Gln Ser Lys Leu Leu Asp Phe Cys Lys Ser 
        195                 200                 205             


Lys Asp Ile Val Leu Val Ala His Ser Ala Leu Gly Thr Gln Arg His 
    210                 215                 220                 


Lys Leu Trp Val Asp Pro Asn Ser Pro Val Leu Leu Glu Asp Pro Val 
225                 230                 235                 240 


Leu Cys Ala Leu Ala Lys Lys His Lys Arg Thr Pro Ala Leu Ile Ala 
                245                 250                 255     


Leu Arg Tyr Gln Leu Gln Arg Gly Val Val Val Leu Ala Lys Ser Tyr 
            260                 265                 270         


Asn Glu Gln Arg Ile Arg Glu Asn Ile Gln Val Phe Glu Phe Gln Leu 
        275                 280                 285             


Thr Ser Glu Asp Met Lys Val Leu Asp Gly Leu Asn Arg Asn Tyr Arg 
    290                 295                 300                 


Tyr Val Val Met Asp Phe Leu Met Asp His Pro Asp Tyr Pro Phe Ser 
305                 310                 315                 320 


Asp Glu Tyr 
            


<210>  5
<211>  316
<212>  PRT
<213>  Homo sapiens

<400>  5

Met Ala Thr Phe Val Glu Leu Ser Thr Lys Ala Lys Met Pro Ile Val 
1               5                   10                  15      


Gly Leu Gly Thr Trp Lys Ser Pro Leu Gly Lys Val Lys Glu Ala Val 
            20                  25                  30          


Lys Val Ala Ile Asp Ala Gly Tyr Arg His Ile Asp Cys Ala Tyr Val 
        35                  40                  45              


Tyr Gln Asn Glu His Glu Val Gly Glu Ala Ile Gln Glu Lys Ile Gln 
    50                  55                  60                  


Glu Lys Ala Val Lys Arg Glu Asp Leu Phe Ile Val Ser Lys Leu Trp 
65                  70                  75                  80  


Pro Thr Phe Phe Glu Arg Pro Leu Val Arg Lys Ala Phe Glu Lys Thr 
                85                  90                  95      


Leu Lys Asp Leu Lys Leu Ser Tyr Leu Asp Val Tyr Leu Ile His Trp 
            100                 105                 110         


Pro Gln Gly Phe Lys Ser Gly Asp Asp Leu Phe Pro Lys Asp Asp Lys 
        115                 120                 125             


Gly Asn Ala Ile Gly Gly Lys Ala Thr Phe Leu Asp Ala Trp Glu Ala 
    130                 135                 140                 


Met Glu Glu Leu Val Asp Glu Gly Leu Val Lys Ala Leu Gly Val Ser 
145                 150                 155                 160 


Asn Phe Ser His Phe Gln Ile Glu Lys Leu Leu Asn Lys Pro Gly Leu 
                165                 170                 175     


Lys Tyr Lys Pro Val Thr Asn Gln Val Glu Cys His Pro Tyr Leu Thr 
            180                 185                 190         


Gln Glu Lys Leu Ile Gln Tyr Cys His Ser Lys Gly Ile Thr Val Thr 
        195                 200                 205             


Ala Tyr Ser Pro Leu Gly Ser Pro Asp Arg Pro Trp Ala Lys Pro Glu 
    210                 215                 220                 


Asp Pro Ser Leu Leu Glu Asp Pro Lys Ile Lys Glu Ile Ala Ala Lys 
225                 230                 235                 240 


His Lys Lys Thr Ala Ala Gln Val Leu Ile Arg Phe His Ile Gln Arg 
                245                 250                 255     


Asn Val Ile Val Ile Pro Lys Ser Val Thr Pro Ala Arg Ile Val Glu 
            260                 265                 270         


Asn Ile Gln Val Phe Asp Phe Lys Leu Ser Asp Glu Glu Met Ala Thr 
        275                 280                 285             


Ile Leu Ser Phe Asn Arg Asn Trp Arg Ala Cys Asn Val Leu Gln Ser 
    290                 295                 300                 


Ser His Leu Glu Asp Tyr Pro Phe Asp Ala Glu Tyr 
305                 310                 315     


<210>  6
<211>  9
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  chemically synthesized - leuprolide


<220>
<221>  MOD_RES
<222>  (1)..(1)
<223>  L-Pyroglutamyl

<220>
<221>  MOD_RES
<222>  (6)..(6)
<223>  D-leucine

<220>
<221>  MOD_RES
<222>  (9)..(9)
<223>  N-ethyl-prolinamide

<400>  6

Xaa His Trp Ser Tyr Xaa Leu Arg Xaa 
1               5                   


