               SEQUENCE LISTING

<110> Bayer Aktiengesellschaft
      Bayer Pharma Aktiengesellschaft
      The Broad Institute, Inc.

<120> SUBSTITUTED MACROCYCLIC INDOLE DERIVATIVES

<130> BHC173064

<150> US62/587935
<151> 2017-11-17

<160> 6

<170> BiSSAP 1.3.6

<210> 1
<211> 519
<212> PRT
<213> Artificial Sequence


<220> 
<223> Modified Sequence

<400> 1
Gly Lys Ile Glu Glu Gly Lys Leu Val Ile Trp Ile Asn Gly Asp Lys 
1               5                   10                  15      
Gly Tyr Asn Gly Leu Ala Glu Val Gly Lys Lys Phe Glu Lys Asp Thr 
            20                  25                  30          
Gly Ile Lys Val Thr Val Glu His Pro Asp Lys Leu Glu Glu Lys Phe 
        35                  40                  45              
Pro Gln Val Ala Ala Thr Gly Asp Gly Pro Asp Ile Ile Phe Trp Ala 
    50                  55                  60                  
His Asp Arg Phe Gly Gly Tyr Ala Gln Ser Gly Leu Leu Ala Glu Ile 
65                  70                  75                  80  
Thr Pro Asp Lys Ala Phe Gln Asp Lys Leu Tyr Pro Phe Thr Trp Asp 
                85                  90                  95      
Ala Val Arg Tyr Asn Gly Lys Leu Ile Ala Tyr Pro Ile Ala Val Glu 
            100                 105                 110         
Ala Leu Ser Leu Ile Tyr Asn Lys Asp Leu Leu Pro Asn Pro Pro Lys 
        115                 120                 125             
Thr Trp Glu Glu Ile Pro Ala Leu Asp Lys Glu Leu Lys Ala Lys Gly 
    130                 135                 140                 
Lys Ser Ala Leu Met Phe Asn Leu Gln Glu Pro Tyr Phe Thr Trp Pro 
145                 150                 155                 160 
Leu Ile Ala Ala Asp Gly Gly Tyr Ala Phe Lys Tyr Glu Asn Gly Lys 
                165                 170                 175     
Tyr Asp Ile Lys Asp Val Gly Val Asp Asn Ala Gly Ala Lys Ala Gly 
            180                 185                 190         
Leu Thr Phe Leu Val Asp Leu Ile Lys Asn Lys His Met Asn Ala Asp 
        195                 200                 205             
Thr Asp Tyr Ser Ile Ala Glu Ala Ala Phe Asn Lys Gly Glu Thr Ala 
    210                 215                 220                 
Met Thr Ile Asn Gly Pro Trp Ala Trp Ser Asn Ile Asp Thr Ser Lys 
225                 230                 235                 240 
Val Asn Tyr Gly Val Thr Val Leu Pro Thr Phe Lys Gly Gln Pro Ser 
                245                 250                 255     
Lys Pro Phe Val Gly Val Leu Ser Ala Gly Ile Asn Ala Ala Ser Pro 
            260                 265                 270         
Asn Lys Glu Leu Ala Lys Glu Phe Leu Glu Asn Tyr Leu Leu Thr Asp 
        275                 280                 285             
Glu Gly Leu Glu Ala Val Asn Lys Asp Lys Pro Leu Gly Ala Val Ala 
    290                 295                 300                 
Leu Lys Ser Tyr Glu Glu Glu Leu Ala Lys Asp Pro Arg Ile Ala Ala 
305                 310                 315                 320 
Thr Met Glu Asn Ala Gln Lys Gly Glu Ile Met Pro Asn Ile Pro Gln 
                325                 330                 335     
Met Ser Ala Phe Trp Tyr Ala Val Arg Thr Ala Val Ile Asn Ala Ala 
            340                 345                 350         
Ser Gly Arg Gln Thr Val Asp Glu Ala Leu Lys Asp Ala Gln Thr Gly 
        355                 360                 365             
Ser Ser Glu Leu Tyr Arg Gln Ser Leu Glu Ile Ile Ser Arg Tyr Leu 
    370                 375                 380                 
Arg Glu Gln Ala Thr Gly Ala Ala Asp Thr Ala Pro Met Gly Ala Ser 
385                 390                 395                 400 
Gly Ala Thr Ser Arg Lys Ala Leu Glu Thr Leu Arg Arg Val Gly Asp 
                405                 410                 415     
Gly Val Gln Arg Asn His Glu Thr Ala Phe Gln Gly Met Leu Arg Lys 
            420                 425                 430         
Leu Asp Ile Lys Asn Glu Asp Asp Val Lys Ser Leu Ser Arg Val Met 
        435                 440                 445             
Ile His Val Phe Ser Asp Gly Val Thr Asn Trp Gly Arg Ile Val Thr 
    450                 455                 460                 
Leu Ile Ser Phe Gly Ala Phe Val Ala Lys His Leu Lys Thr Ile Asn 
465                 470                 475                 480 
Gln Glu Ser Cys Ile Glu Pro Leu Ala Glu Ser Ile Thr Asp Val Leu 
                485                 490                 495     
Val Arg Thr Lys Arg Asp Trp Leu Val Lys Gln Arg Gly Trp Asp Gly 
            500                 505                 510         
Phe Val Glu Phe Phe His Val 
        515                 

<210> 2
<211> 26
<212> PRT
<213> Artificial Sequence


<220> 
<221> MOD_RES
<222> 1
<223> Biotin-PEG-PEG-PEG-PEG

<220> 
<223> Modified Sequence

<220> 
<221> MOD_RES
<222> 8
<223> Norvalin

<220> 
<221> MOD_RES
<222> 26
<223> AMIDATION

<400> 2
Pro Ala Glu Leu Glu Val Glu Val Ala Thr Gln Leu Arg Arg Phe Gly 
1               5                   10                  15      
Asp Lys Leu Asn Phe Arg Gln Lys Leu Leu 
            20                  25      

<210> 3
<211> 212
<212> PRT
<213> Artificial Sequence


<220> 
<223> Modified Sequence

<220> 
<221> MOD_RES
<222> 212
<223> HHHHHH

<400> 3
Met Ser Gln Ser Asn Arg Glu Leu Val Val Asp Phe Leu Ser Tyr Lys 
1               5                   10                  15      
Leu Ser Gln Lys Gly Tyr Ser Trp Ser Gln Phe Ser Asp Val Glu Glu 
            20                  25                  30          
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Ser Glu Met Glu Thr Pro 
        35                  40                  45              
Ser Ala Ile Asn Gly Asn Pro Ser Trp His Leu Ala Asp Ser Pro Ala 
    50                  55                  60                  
Val Asn Gly Ala Thr Gly His Ser Ser Ser Leu Asp Ala Arg Glu Val 
65                  70                  75                  80  
Ile Pro Met Ala Ala Val Lys Gln Ala Leu Arg Glu Ala Gly Asp Glu 
                85                  90                  95      
Phe Glu Leu Arg Tyr Arg Arg Ala Phe Ser Asp Leu Thr Ser Gln Leu 
            100                 105                 110         
His Ile Thr Pro Gly Thr Ala Tyr Gln Ser Phe Glu Gln Val Val Asn 
        115                 120                 125             
Glu Leu Phe Arg Asp Gly Val Asn Trp Gly Arg Ile Val Ala Phe Phe 
    130                 135                 140                 
Ser Phe Gly Gly Ala Leu Cys Val Glu Ser Val Asp Lys Glu Met Gln 
145                 150                 155                 160 
Val Leu Val Ser Arg Ile Ala Ala Trp Met Ala Thr Tyr Leu Asn Asp 
                165                 170                 175     
His Leu Glu Pro Trp Ile Gln Glu Asn Gly Gly Trp Asp Thr Phe Val 
            180                 185                 190         
Glu Leu Tyr Gly Asn Asn Ala Ala Ala Glu Ser Arg Lys Gly Gln Glu 
        195                 200                 205             
Arg Phe Asn Arg 
    210         

<210> 4
<211> 25
<212> PRT
<213> Artificial Sequence


<220> 
<221> MOD_RES
<222> 1
<223> Biotin-PEG-PEG-PEG-PEG

<220> 
<223> Modified Sequence

<220> 
<221> MOD_RES
<222> 15
<223> Norleucin

<220> 
<221> MOD_RES
<222> 25
<223> AMIDATION

<400> 4
Asn Leu Trp Ala Ala Gln Arg Tyr Gly Arg Glu Leu Arg Arg Leu Ser 
1               5                   10                  15      
Asp Glu Phe Val Asp Ser Phe Lys Lys 
            20                  25  

<210> 5
<211> 211
<212> PRT
<213> Artificial Sequence


<220> 
<223> Modified Sequence

<220> 
<221> MOD_RES
<222> 211
<223> HHHHHH

<400> 5
Met Ala His Ala Gly Arg Thr Gly Tyr Asp Asn Arg Glu Ile Val Met 
1               5                   10                  15      
Lys Tyr Ile His Tyr Lys Leu Ser Gln Arg Gly Tyr Glu Trp Asp Ala 
            20                  25                  30          
Gly Asp Val Gly Ala Ala Pro Pro Gly Ala Ala Pro Ala Pro Gly Ile 
        35                  40                  45              
Phe Ser Ser Gln Pro Gly His Thr Pro His Pro Ala Ala Ser Arg Asp 
    50                  55                  60                  
Pro Val Ala Arg Thr Ser Pro Leu Gln Thr Pro Ala Ala Pro Gly Ala 
65                  70                  75                  80  
Ala Ala Gly Pro Ala Leu Ser Pro Val Pro Pro Val Val His Leu Thr 
                85                  90                  95      
Leu Arg Gln Ala Gly Asp Asp Phe Ser Arg Arg Tyr Arg Arg Asp Phe 
            100                 105                 110         
Ala Glu Met Ser Ser Gln Leu His Leu Thr Pro Phe Thr Ala Arg Gly 
        115                 120                 125             
Arg Phe Ala Thr Val Val Glu Glu Leu Phe Arg Asp Gly Val Asn Trp 
    130                 135                 140                 
Gly Arg Ile Val Ala Phe Phe Glu Phe Gly Gly Val Met Cys Val Glu 
145                 150                 155                 160 
Ser Val Asn Arg Glu Met Ser Pro Leu Val Asp Asn Ile Ala Leu Trp 
                165                 170                 175     
Met Thr Glu Tyr Leu Asn Arg His Leu His Thr Trp Ile Gln Asp Asn 
            180                 185                 190         
Gly Gly Trp Asp Ala Phe Val Glu Leu Tyr Gly Pro Ser Met Arg Pro 
        195                 200                 205             
Leu Phe Asp 
    210     

<210> 6
<211> 518
<212> PRT
<213> Artificial Sequence


<220> 
<223> Modified Sequence

<220> 
<221> MOD_RES
<222> 194
<223> K194A

<220> 
<221> MOD_RES
<222> 197
<223> K197A

<220> 
<221> MOD_RES
<222> 201
<223> R201A

<400> 6
Gly Lys Ile Glu Glu Gly Lys Leu Val Ile Trp Ile Asn Gly Asp Lys 
1               5                   10                  15      
Gly Tyr Asn Gly Leu Ala Glu Val Gly Lys Lys Phe Glu Lys Asp Thr 
            20                  25                  30          
Gly Ile Lys Val Thr Val Glu His Pro Asp Lys Leu Glu Glu Lys Phe 
        35                  40                  45              
Pro Gln Val Ala Ala Thr Gly Asp Gly Pro Asp Ile Ile Phe Trp Ala 
    50                  55                  60                  
His Asp Arg Phe Gly Gly Tyr Ala Gln Ser Gly Leu Leu Ala Glu Ile 
65                  70                  75                  80  
Thr Pro Asp Lys Ala Phe Gln Asp Lys Leu Tyr Pro Phe Thr Trp Asp 
                85                  90                  95      
Ala Val Arg Tyr Asn Gly Lys Leu Ile Ala Tyr Pro Ile Ala Val Glu 
            100                 105                 110         
Ala Leu Ser Leu Ile Tyr Asn Lys Asp Leu Leu Pro Asn Pro Pro Lys 
        115                 120                 125             
Thr Trp Glu Glu Ile Pro Ala Leu Asp Lys Glu Leu Lys Ala Lys Gly 
    130                 135                 140                 
Lys Ser Ala Leu Met Phe Asn Leu Gln Glu Pro Tyr Phe Thr Trp Pro 
145                 150                 155                 160 
Leu Ile Ala Ala Asp Gly Gly Tyr Ala Phe Lys Tyr Asn Asn Gly Lys 
                165                 170                 175     
Tyr Asp Ile Lys Asp Val Gly Val Asp Asn Ala Gly Ala Lys Ala Gly 
            180                 185                 190         
Leu Thr Phe Leu Val Asp Leu Ile Lys Asn Lys His Met Asn Ala Asp 
        195                 200                 205             
Thr Asp Tyr Ser Ile Ala Glu Ala Ala Phe Asn Lys Gly Glu Thr Ala 
    210                 215                 220                 
Met Thr Ile Asn Gly Pro Trp Ala Trp Ser Asn Ile Asp Thr Ser Lys 
225                 230                 235                 240 
Val Asn Tyr Gly Val Thr Val Leu Pro Thr Phe Lys Gly Gln Pro Ser 
                245                 250                 255     
Lys Pro Phe Val Gly Val Leu Ser Ala Gly Ile Asn Ala Ala Ser Pro 
            260                 265                 270         
Asn Lys Glu Leu Ala Lys Glu Phe Leu Glu Asn Tyr Leu Leu Thr Asp 
        275                 280                 285             
Glu Gly Leu Glu Ala Val Asn Lys Asp Lys Pro Leu Gly Ala Val Ala 
    290                 295                 300                 
Leu Lys Ser Tyr Glu Glu Glu Leu Ala Lys Asp Pro Arg Ile Ala Ala 
305                 310                 315                 320 
Thr Met Glu Asn Ala Gln Lys Gly Glu Ile Met Pro Asn Ile Pro Gln 
                325                 330                 335     
Met Ser Ala Phe Trp Tyr Ala Val Arg Thr Ala Val Ile Asn Ala Ala 
            340                 345                 350         
Ser Gly Arg Gln Thr Val Asp Glu Ala Leu Lys Asp Ala Gln Thr Gly 
        355                 360                 365             
Ser Glu Leu Tyr Arg Gln Ser Leu Glu Ile Ile Ser Arg Tyr Leu Arg 
    370                 375                 380                 
Glu Gln Ala Thr Gly Ala Ala Asp Thr Ala Pro Met Gly Ala Ser Gly 
385                 390                 395                 400 
Ala Thr Ser Arg Lys Ala Leu Glu Thr Leu Arg Arg Val Gly Asp Gly 
                405                 410                 415     
Val Gln Arg Asn His Glu Thr Ala Phe Gln Gly Met Leu Arg Lys Leu 
            420                 425                 430         
Asp Ile Lys Asn Glu Asp Asp Val Lys Ser Leu Ser Arg Val Met Ile 
        435                 440                 445             
His Val Phe Ser Asp Gly Val Thr Asn Trp Gly Arg Ile Val Thr Leu 
    450                 455                 460                 
Ile Ser Phe Gly Ala Phe Val Ala Lys His Leu Lys Thr Ile Asn Gln 
465                 470                 475                 480 
Glu Ser Cys Ile Glu Pro Leu Ala Glu Ser Ile Thr Asp Val Leu Val 
                485                 490                 495     
Arg Thr Lys Arg Asp Trp Leu Val Lys Gln Arg Gly Trp Asp Gly Phe 
            500                 505                 510         
Val Glu Phe Phe His Val 
        515             

