IP Library › Granted Patent US 12,466,853
Granted Patent B2
US 12,466,853 · App. 18/494,623 · Granted Nov 11, 2025

Selective targeting of apoptosis proteins by structurally-stabilized and/or cysteine-reactive NOXA peptides

Inventors: Loren D. Walensky (Newton, MA); Gregory H. Bird (Pelham, NH); Rachel Guerra (Cambridge, MA); Edward Harvey (Weston, MA)
Assignee: Dana-Farber Cancer Institute, Inc.
C07K7/08A61K38/00A61K45/06
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Quick Facts
Patent No.
US 12,466,853
App. No.
18/494,623
Granted
Nov 11, 2025
Kind
B2
Abstract

This disclosure features structurally-stabilized and/or cysteine-reactive peptide inhibitors for selective targeting of BFL-1, or dual targeting of BFL-1 and MCL-1. Also disclosed are methods of using such structurally-stabilized and cysteine-reactive peptides in the treatment of BFL-1- and/or MCL-1-expressing or -dependent cancers or diseases of cellular excess (e.g., autoimmune or inflammatory conditions). Also provided are combination therapies comprising such structurally-stabilized and/or cysteine-reactive peptides and inhibitors of the DNA damage response pathway, such as an ATM kinase inhibitor, ATR kinase inhibitor, CHK1/2 inhibitor, or PARP inhibitor; or an inhibitor of MCL-1, or a selective inhibitor of BCL-2, or an inhibitor of BCL-2/BCL-XL, for the treatment of BFL-1-expressing or -dependent cancers (e.g., AML), BFL-1 and MCL-1-expressing or -dependent cancers, or diseases of cellular excess (e.g., autoimmune or inflammatory conditions).

Claims (129)

1 . A peptide that covalently binds to BFL-1/A1, the peptide comprising an electrophilic warhead and the amino acid sequence set forth in any one of SEQ ID NOs: 94-109 except for zero to three amino acid substitutions, wherein SEQ ID NOs: 94-109 have the amino acid sequences set forth below:

(SEQ ID NO: 94)

ATQLRRAGDKLNFRQ;

(SEQ ID NO: 95)

ATQLRRFGDKANFRQ;

(SEQ ID NO: 96)

ATQLREFGDKLNFRQ;

(SEQ ID NO: 97)

ATQLRRFGDKLNFEQ;

(SEQ ID NO: 98)

AAQLRAFGAKLNAA;

(SEQ ID NO: 99)

AAQLRAFGAKLNAAAA;

(SEQ ID NO: 100)

AAQLRAFGAKLNAE;

(SEQ ID NO: 101)

AAQLRAFGAKLNAEAA;

(SEQ ID NO: 102)

AAQLREFGAKLNAA;

(SEQ ID NO: 103)

AAQLREFGAKLNAAAA;

(SEQ ID NO: 104)

AAQLRAFGDKLNAA;

(SEQ ID NO: 105)

AAQLRAFGDKLNAAAA;

(SEQ ID NO: 106)

AAQLRAFGDKLNAE;

(SEQ ID NO: 107)

AAQLRAFGDKLNAEAA;

(SEQ ID NO: 108)

AAQLREFGDKLNAA;

or

(SEQ ID NO: 109)

AAQLREFGDKLNAAAA,

wherein the peptide selectively binds BFL-1/A1 over MCL-1;

wherein if one or three amino acid substitutions are present, one amino acid substitution is a glutamic acid at position 6 or 14, an aspartic acid at position 12, a leucine at position 15, or an L-alanine, D-alanine, or a-aminoisobutyric acid at position 1, 2, 5, 7, 8, 11, 13, or 14; and

wherein if two or three amino acid substitutions are present, two amino acid substitutions are with non-natural amino acids with olefinic side chains at positions 3 and 10 that are cross-linked.

2 . A pharmaceutical composition comprising the peptide of claim 1 , and a pharmaceutically acceptable carrier.

3 . A peptide that covalently binds to BFL-1/A1, the peptide comprising the amino acid sequence set forth in any one of SEQ ID NOs: 60-75 except for one amino acid substitution, wherein SEQ ID NOs: 60-75 have the amino acid sequence set forth below:

(SEQ ID NO: 60)

JAT X 1 LRRAGD X 2 LNFRQ;

(SEQ ID NO: 61)

JAT X 1 LRRFGD X 2 ANFRQ;

(SEQ ID NO: 62)

JAT X 1 LREFGD X 2 LNFRQ;

(SEQ ID NO: 63)

JAT X 1 LRRFGD X 2 LNFEQ;

(SEQ ID NO: 64)

JAA X 1 LRAFGA X 2 LNAA;

(SEQ ID NO: 65)

JAA X 1 LRAFGA X 2 LNAAAA;

(SEQ ID NO: 66)

JAA X 1 LRAFGA X 2 LNAE;

(SEQ ID NO: 67)

JAA X 1 LRAFGA X 2 LNAEAA;

(SEQ ID NO: 68)

JAA X 1 LREFGA X 2 LNAA;

(SEQ ID NO: 69)

JAA X 1 LREFGA X 2 LNAAAA;

(SEQ ID NO: 70)

JAA X 1 LRAFGD X 2 LNAA;

(SEQ ID NO: 71)

JAA X 1 LRAFGD X 2 LNAAAA;

(SEQ ID NO: 72)

JAA X 1 LRAFGD X 2 LNAE;

(SEQ ID NO: 73)

JAA X 1 LRAFGD X 2 LNAEAA;

(SEQ ID NO: 74)

JAA X 1 LREFGD X 2 LNAA;

or

(SEQ ID NO: 75)

JAA X 1 LREFGD X 2 LNAAAA,

wherein the peptide covalently binds BFL-1/A1 and non-covalently binds MCL-1;

wherein J is an electrophilic warhead; wherein X 1 and X 2 are non-natural amino acids with olefinic side chains, and wherein X 1 is cross-linked to X 2 ; wherein the amino acid substitution is a glutamic acid at position 7 or 15, an aspartic acid at position 13, a leucine at position 16, or an L-alanine, D-alanine, or α-aminoisobutyric acid at position 2, 3, 6, 8, 9, 12, 14, or 15.

4 . The peptide of claim 3 , wherein X 1 is R-octenyl alanine and X 2 is S-pentenyl alanine; and wherein X 1 is cross-linked to X 2 .

5 . The peptide of claim 3 , wherein the electrophilic warhead is a cysteine-reactive acrylamide D-nipecotic acid moiety.

6 . The peptide of claim 3 , wherein the peptide is 35 amino acids or less in length.

7 . A pharmaceutical composition comprising the peptide of claim 3 , and a pharmaceutically acceptable carrier.

8 . A peptide that covalently binds to BFL-1/A1, the peptide comprising an amino acid sequence set forth below:

(SEQ ID NO: 61)

JAT X 1 LRRFGD X 2 ANFRQ;

(SEQ ID NO: 63)

JAT X 1 LRRFGD X 2 LNFEQ;

(SEQ ID NO: 64)

JAA X 1 LRAFGA X 2 LNAA;

(SEQ ID NO: 65)

JAA X 1 LRAFGA X 2 LNAAAA;

(SEQ ID NO: 66)

JAA X 1 LRAFGA X 2 LNAE;

(SEQ ID NO: 67)

JAA X 1 LRAFGA X 2 LNAEAA;

(SEQ ID NO: 68)

JAA X 1 LREFGA X 2 LNAA;

(SEQ ID NO: 69)

JAA X 1 LREFGA X 2 LNAAAA;

(SEQ ID NO: 70)

JAA X 1 LRAFGD X 2 LNAA;

(SEQ ID NO: 71)

JAA X 1 LRAFGD X 2 LNAAAA;

(SEQ ID NO: 72)

JAA X 1 LRAFGD X 2 LNAE;

(SEQ ID NO: 73)

JAA X 1 LRAFGD X 2 LNAEAA;

(SEQ ID NO: 74)

JAA X 1 LREFGD X 2 LNAA;

or

(SEQ ID NO: 75)

JAA X 1 LREFGD X 2 LNAAAA,

wherein J is an electrophilic warhead; wherein X 1 and X 2 are non-natural amino acids with olefinic side chains, and wherein X 1 is cross-linked to X 2 .

9 . The peptide of claim 8 , wherein the peptide comprises the sequence JAAX 1 LREFGAX 2 LNAA (SEQ ID NO:68), wherein J is an electrophilic warhead; wherein X 1 is R-octenyl alanine and X 2 is S-pentenyl alanine; and wherein X 1 is cross-linked to X 2 .

10 . The peptide of claim 8 , wherein the peptide comprises the sequence JAAX 1 LREFGAX 2 LNAAAA (SEQ ID NO:69), wherein J is an electrophilic warhead; wherein X 1 is R-octenyl alanine and X 2 is S-pentenyl alanine; and wherein X 1 is cross-linked to X 2 .

11 . The peptide of claim 8 , wherein the peptide comprises the sequence JATX 1 LRRFGDX 2 ANFRQ (SEQ ID NO:61), wherein J is an electrophilic warhead; wherein X 1 is R-octenyl alanine and X 2 is S-pentenyl alanine; and wherein X 1 is cross-linked to X 2 .

12 . The peptide of claim 8 , wherein the peptide comprises the sequence JATX 1 LRRFGDX 2 LNFEQ (SEQ ID NO:63), wherein J is an electrophilic warhead; wherein X 1 is R-octenyl alanine and X 2 is S-pentenyl alanine; and wherein X 1 is cross-linked to X 2 .

13 . The peptide of claim 8 , wherein the peptide is 35 amino acids or less in length.

14 . The peptide of claim 8 , wherein the peptide consists of the amino acid sequence of any one of SEQ ID NOs: 61 and 63-75.

15 . The peptide of claim 8 , wherein the electrophilic warhead is a cysteine-reactive acrylamide D-nipecotic acid moiety.

16 . The peptide of claim 14 , wherein the electrophilic warhead is a cysteine-reactive acrylamide D-nipecotic acid moiety.

17 . A pharmaceutical composition comprising the peptide of claim 8 , and a pharmaceutically acceptable carrier.

18 . A stabilized peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 40 to 53.

19 . A pharmaceutical composition comprising the stabilized peptide of claim 18 , and a pharmaceutically acceptable carrier.

20 . A combination therapy for treating a BFL-1/A1-expressing disease, a BFL-1/A1-dependent disease, an MCL-1-expressing disease, or an MCL-1-dependent disease comprising a peptide of claim 1 and an inhibitor of the DNA damage response pathway.

21 . A combination therapy for treating a BCL-XL-, BCL-2-, and/or MCL-1 expressing and a BFL-1/A1-expressing disease, or a BCL-XL-, BCL-2, and/or MCL-1-dependent and BFL-1/A1-dependent disease in a human subject in need thereof, comprising a peptide of claim 1 and an inhibitor of BCL-XL, an inhibitor of BCL-2, and/or an inhibitor of MCL-1.

22 . A combination therapy for treating a BFL-1/A1-expressing disease, a BFL-1/A1-dependent disease, an MCL-1-expressing disease, or an MCL-1-dependent disease comprising a peptide of claim 8 and an inhibitor of the DNA damage response pathway.

23 . The combination therapy of claim 22 , wherein the inhibitor of the DNA damage response pathway is AZD0156.

24 . A combination therapy for treating a BCL-XL-, BCL-2-, and/or MCL-1 expressing and a BFL-1/A1-expressing disease, or a BCL-XL-, BCL-2, and/or MCL-1-dependent and BFL-1/A1-dependent disease in a human subject in need thereof, comprising a peptide of claim 8 and an inhibitor of BCL-XL, an inhibitor of BCL-2, and/or an inhibitor of MCL-1.

25 . A combination therapy for treating a BFL-1-expressing disease, a BFL-1-dependent disease, an MCL-1-expressing disease, an MCL-1-dependent disease comprising a stabilized peptide of claim 18 and an inhibitor of a DNA damage response pathway member.

26 . A method of treating a BFL-1/A1-expressing disease or a BFL-1/A1-dependent disease in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of the peptide of claim 1 .

27 . A method of treating a BFL-1/A1-expressing disease or a BFL-1/A1-dependent disease in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of the peptide of claim 8 .

28 . A method of treating an MCL-1-expressing and a BFL-1/A1-expressing disease, or an MCL-1-dependent and a BFL-1/A1-dependent disease in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of the stabilized peptide of claim 18 .

Assignments (2)
CONFIRMATORY LICENSE Recorded Jan 17, 2024
From: DANA-FARBER CANCER INST
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 066340/0499 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 25, 2023
From: WALENSKY, LOREN D.; BIRD, GREGORY H.; GUERRA, RACHEL; HARVEY, EDWARD
To: DANA-FARBER CANCER INSTITUTE, INC.
Reel/Frame 065348/0254 →
Continuity (4)
Division 16766201
Provisional Application 62599229 · Dec 15, 2017
Related Publication 20240132544A1 · Apr 25, 2024
Related Publication 20240228539A9 · Jul 11, 2024
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