Methods of identifying drug-modulated polypeptide targets for degradation

Abstract

In one aspect, the invention features a method for identifying a drug-modulated polypeptide substrate of cereblon (CRBN). In another aspect, the invention features a method of identifying a polypeptide target of a modulator of CRBN. In yet another aspect, the invention provides methods of monitoring or characterizing the sensitivity of a subject to a modulator of CRBN.

What is claimed is: 
     
         1 . A method of identifying a cell resistant to a modulator of cereblon (CRBN), the method comprising detecting a mutation in the sequence of a region in a IKZF3 polynucleotide relative to a IKZF3 reference sequence, wherein said region encodes amino acids 148, 151, 152, 153, 155, 164 and 168 of a IKZF3 polypeptide in said cell, and wherein the mutation in one or more of said encoded amino acids indicates that the cell is resistant to a modulator of CRBN. 
     
     
         2 . A method of characterizing or monitoring sensitivity of a subject to a modulator of cereblon (CRBN), the method comprising detecting a mutation in the sequence of a region in an IKZF3 polynucleotide in a biological sample obtained from the subject relative to a IKZF3 reference sequence, wherein said region encodes amino acids 148, 151, 152, 153, 155, 164 and 168 of a IKZF3 polypeptide, and wherein detection of a mutation in one or more of said encoded amino acids is indicative of resistance to a modulator of CRBN and failure to detect a mutation is indicative of sensitivity to a modulator of CRBN. 
     
     
         3 . The method of  claim 2 , further comprising administering to the subject an amount of a modulator of CRBN prior to detecting the mutation. 
     
     
         4 . A method of selecting a subject for treatment with an alternative to a modulator of cereblon (CRBN), the method comprising detecting a mutation in the sequence of a region in an IKZF3 polynucleotide in a biological sample obtained from the subject relative to a IKZF3 reference sequence, wherein said region encodes amino acids 148, 151, 152, 153, 155, 164 and 168 of a IKZF3 polypeptide, and wherein a subject having a mutation in one or more of said encoded amino acids is selected for treatment with an alternative to a modulator of CRBN. 
     
     
         5 . The method of  claim 1 , wherein the modulator of CRBN is lenalidomide, thalidomide, or pomalidomide. 
     
     
         6 . The method of  claim 2 , wherein the modulator of CRBN is lenalidomide, thalidomide, or pomalidomide. 
     
     
         7 . The method of  claim 4 , wherein the modulator of CRBN is lenalidomide, thalidomide, or pomalidomide. 
     
     
         8 . The method of  claim 1 , wherein the subject has one or more of a B cell neoplasia or related condition, a plasma cell malignancy, multiple myeloma, or a myelodysplastic syndrome. 
     
     
         9 . The method of  claim 2 , wherein the subject has one or more of a B cell neoplasia or related condition, a plasma cell malignancy, multiple myeloma, or a myelodysplastic syndrome. 
     
     
         10 . The method of  claim 4 , wherein the subject has one or more of a B cell neoplasia or related condition, a plasma cell malignancy, multiple myeloma, or a myelodysplastic syndrome. 
     
     
         11 . The method of  claim 2 , wherein the biological sample is blood, bone marrow, or lymphoid tissue. 
     
     
         12 . The method of  claim 4 , wherein the biological sample is blood, bone marrow, or lymphoid tissue.