Stabilized peptide-mediated targeted protein degradation

Patent metadata

Field	Value
Publication number	US-2024140999-A1
Application number	US-202318113539-A
Country	US
Kind code	A1
Filing date	Feb 23, 2023
Priority date	Dec 15, 2017
Publication date	May 2, 2024
Grant date	—

Abstract

The present application describes stapled peptide degron chimeras, which act as protein degradation inducing moieties, either by combining a stapled peptide that binds a disease-related protein with a small molecule degron, such as a cereblon- or VHL-binding small molecule as the degron, or a polypeptide sequence degron, such as a Cop1-binding Trib peptide as the degron; or by combining a stapled peptide degron with a peptide, such as a stapled peptide, or a small molecule that binds a disease-related protein. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of stapled peptide degron chimeras which can be utilized in the treatment of proliferative disorders or other conditions whereby elimination of a disease-causing or disease-related protein would have a therapeutic benefit. The present application also provides methods for making compounds of the application and intermediates thereof.

First claim

1 . A chimera, comprising:
a first moiety attached to a second moiety; wherein the first moiety binds to a first protein targeted for degradation; wherein the second moiety binds to a second protein; and wherein the second protein is a protein degrader.

2 .- 5 . (canceled)

6 . The chimera of claim 1 , wherein the first moiety comprises a stapled peptide that binds to the first protein targeted for degradation.

7 . The chimera of claim 6 , wherein the stapled peptide does not comprise a Bcl-2 homology 3 (BH3) domain polypeptide.

8 .- 11 . (canceled)

12 . The chimera of claim 1 , wherein the first moiety comprises a small molecule that binds to the first protein targeted for degradation.

13 . The chimera of claim 1 , wherein the second moiety comprises a peptide degron that binds to the protein degrader.

14 . The chimera of claim 1 , wherein the second moiety comprises a stapled peptide that binds to the protein degrader.

15 . The chimera of claim 1 , wherein the second moiety comprises a small molecule that binds to the protein degrader.

16 . The chimera of claim 1 , wherein the second moiety comprises a stapled peptide that binds to the protein degrader, and wherein the first moiety is attached to (i) the N-terminus of the second moiety, (ii) the C-terminus of the second moiety, or (iii) an internal amino acid position of the second moiety.

17 .- 19 . (canceled)

20 . A method of treating a disease or disorder driven by a pathologic peptide or protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the chimera of claim 1 .

21 . A chimeric polypeptide comprising a stapled peptide and a peptide that binds a WD40-repeat protein that is a substrate adaptor for an E3 ubiquitin ligase, wherein the peptide comprises a modified version of a natural binding sequence or a natural binding consensus sequence of an amino acid sequence that binds to the WD40-repeat protein, wherein the modified version comprises at least one amino acid substitution, at least one amino acid deletion, at least one amino acid insertion, or any combination thereof within the natural binding consensus sequence.

22 .- 44 . (canceled)

45 . A modified protein of a first protein that comprises a structurally disordered region, wherein the modified protein differs from the first protein in that the structurally disordered region comprises a peptide that binds a WD40-repeat protein that is a substrate adaptor for an E3 ubiquitin ligase, the peptide comprising a modified version of a natural binding sequence or a natural binding consensus sequence, wherein the modified version comprises at least one amino acid substitution, at least one amino acid deletion, at least one amino acid insertion, or any combination thereof within the natural binding consensus sequence.

46 .- 62 . (canceled)

63 . A method of treating a disease or disorder driven by a pathologic peptide or protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the chimeric polypeptide of claim 21 .

64 . A peptide small molecule fusion comprising: (a) a protein-targeting stapled peptide and a thalidomide degron moiety; or (b) a protein-targeting stapled peptide and a Von Hippel-Lindau (VHL) degron moiety.

65 .- 76 . (canceled)

77 . A method of treating a disease or disorder driven by a pathologic peptide or protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the peptide small molecule fusion of claim 64 .

78 .- 90 . (canceled)

91 . A peptide that binds Constitutive Photomorphogenic 1 (Cop1) protein, wherein the peptide comprises a modified version of the amino acid sequence DQIVPEY (SEQ ID NO:25), wherein the modified version comprises at least one amino acid substitution, at least one amino acid deletion, at least one amino acid insertion, or any combination thereof in SEQ ID NO:25, but wherein if the modified version consists of a single amino acid substitution, then the amino acid substitution is not to A or R at any one of positions 1 to 7 of SEQ ID NO:25, or to V at position 4 of SEQ ID NO:25.

92 .- 107 . (canceled)

108 . A chimeric fusion polypeptide comprising a protein-targeting stapled peptide and a peptide of claim 91 .

109 .- 114 . (canceled)

115 . A method of treating a disease or disorder driven by a pathologic peptide or protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the chimeric fusion polypeptide of claim 108 .

116 . A method of treating a disease or disorder driven by a pathologic peptide or protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the modified protein of claim 45 .

117 . A pharmaceutical composition comprising the chimera of claim 1 and a pharmaceutically acceptable carrier and/or vehicle.

118 . A pharmaceutical composition comprising the chimeric polypeptide of claim 21 and a pharmaceutically acceptable carrier and/or vehicle.

119 . A pharmaceutical composition comprising the modified protein of claim 45 and a pharmaceutically acceptable carrier and/or vehicle.

120 . A pharmaceutical composition comprising the peptide of claim 91 and a pharmaceutically acceptable carrier and/or vehicle.

121 . A pharmaceutical composition comprising the chimeric fusion polypeptide of claim 108 and a pharmaceutically acceptable carrier and/or vehicle.

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Walensky Loren D
• Bird Gregory H
• Cathcart Ann Morgan
• Mourtada Rida
• Herce Henry D
• Bradner James E

Classifications

• C07K2319/00

  Fusion polypeptide · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/17

  from animals; from humans {(enzyme inhibitors A61K38/005)} · CPC title

• A61K38/07

  Tetrapeptides · CPC title

• A61K38/08

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title