Methods of identifying drug-modulated polypeptide targets for degradation

Patent metadata

Field	Value
Publication number	US-2022017938-A1
Application number	US-202117496578-A
Country	US
Kind code	A1
Filing date	Oct 7, 2021
Priority date	Sep 11, 2015
Publication date	Jan 20, 2022
Grant date	—

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.

First claim

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.

Assignees

• Broad Inst Inc
• Harvard College
• Brigham & Womens Hospital Inc

Inventors

• Mikkelsen Tarjei
• Ebert Benjamin Levine
• Sievers Quinlan

Classifications

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/4035

  Isoindoles, e.g. phthalimide · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12N5/0635

  B lymphocytes · CPC title