US 12,466,853 B2
Selective targeting of apoptosis proteins by structurally-stabilized and/or cysteine-reactive NOXA peptides
Loren D. Walensky, Newton, MA (US); Gregory H. Bird, Pelham, NH (US); Rachel Guerra, Cambridge, MA (US); and Edward Harvey, Weston, MA (US)
Assigned to Dana-Farber Cancer Institute, Inc., Boston, MA (US)
Filed by Dana-Farber Cancer Institute, Inc., Boston, MA (US)
Filed on Oct. 25, 2023, as Appl. No. 18/494,623.
Application 18/494,623 is a division of application No. 16/766,201, granted, now 11,834,520, previously published as PCT/US2018/065438, filed on Dec. 13, 2018.
Claims priority of provisional application 62/599,229, filed on Dec. 15, 2017.
Prior Publication US 2024/0132544 A1, Apr. 25, 2024
Prior Publication US 2024/0228539 A9, Jul. 11, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. C07K 7/08 (2006.01); A61K 38/00 (2006.01); A61K 45/06 (2006.01)
CPC C07K 7/08 (2013.01) [A61K 38/00 (2013.01); A61K 45/06 (2013.01)] 28 Claims
 
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.