US 2026/0226104 A1 · SELECTIVE TARGETING OF APOPTOSIS PROTEINS BY STRUCTURALLY-STABILIZED AND/OR CYSTEINE-REACTIVE NOXA PEPTIDES

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).

Claims24

Dependent claims

A peptide comprising:

(A) (i) an electrophilic warhead;
and
(ii) a modified amino acid sequence of the sequence set forth in SEQ ID NO:39, wherein the modified amino acid sequence:
is at least five amino acids in length;
comprises at least one peptide structure stabilizing modification and wherein the modified amino acid sequence comprises substitution of one or more amino acids corresponding to the sequence set forth in SEQ ID NO:39 by another amino acid, and
wherein the peptide:
(a) binds BFL-1/A1;
or
(b) binds BFL-1/A1 and MCL-1;
or
(B) an amino acid sequence selected from the group consisting of SEQ ID NOs:
40 to 53.

9 more elements

A peptide comprising:

(i) an electrophilic warhead;
and
(ii) five or more amino acids of:
A0B0C0D0E0A1B1C1D1E1A2B2C2D2E2 (SEQ ID NO:93), wherein:
(a) A0 is absent, A, D-alanine, α-aminoisobutyric acid, or a staple/stitch position;
(b) B0 is absent, T, A, D-alanine, α-aminoisobutyric acid, I, M, B (norleucine), or a staple/stitch position;
(c) C0 is absent, Q, A, D-alanine, α-aminoisobutyric acid, or a staple/stitch position;
(d) D0 is absent, L, A, D-alanine, α-aminoisobutyric acid, I, or F;
(e) E0 is R, A, D-alanine, α-aminoisobutyric acid, K, T, or a staple/stitch position;
(f) A1 is R, A, D-alanine, α-aminoisobutyric acid, E, or a staple/stitch position;
(g) B1 is F, A, D-alanine, α-aminoisobutyric acid, I, L, V, or a staple/stitch position;
(h) C1 is G, A, D-alanine, α-aminoisobutyric acid, or a staple/stitch position;
(i) D1 is D;
(j) E1 is absent, K, A, D-alanine, α-aminoisobutyric acid, or a staple/stitch position;
(k) A2 is absent, L, A, D-alanine, α-aminoisobutyric acid, W, V, or a staple/stitch position;
(l) B2 is absent, N, A, D-alanine, α-aminoisobutyric acid, S, D, or a staple/stitch position;
(m) C2 is absent, F, A, L, D-alanine, α-aminoisobutyric acid, or a staple/stitch position;
(n) D2 is absent, R, A, D-alanine, α-aminoisobutyric acid, E, or a staple/stitch position;
and
(o) E2 is absent, Q, A, D-alanine, α-aminoisobutyric acid, L, or a staple/stitch position,
wherein the peptide:
(a) binds BFL-1/A1;
or
(b) binds BFL-1/A1 and MCL-1.

21 more elements

A peptide that covalently binds to BFL-1/A1, the peptide comprising:

(A) an electrophilic warhead and a sequence that is at least 14% identical to an amino acid sequence 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;
or
(B) an amino acid sequence set forth below:
(SEQ ID NO:
60)
JATX1LRRAGDX2LNFRQ;
(SEQ ID NO:
61)
JATX1LRRFGDX2ANFRQ;
(SEQ ID NO:
62)
JATX1LREFGDX2LNFRQ;
(SEQ ID NO:
63)
JATX1LRRFGDX2LNFEQ;
(SEQ ID NO:
64)
JAAX1LRAFGAX2LNAA;
(SEQ ID NO:
65)
JAAX1LRAFGAX2LNAAAA;
(SEQ ID NO:
66)
JAAX1LRAFGAX2LNAE;
(SEQ ID NO:
67)
JAAX1LRAFGAX2LNAEAA;
(SEQ ID NO:
68)
JAAX1LREFGAX2LNAA;
(SEQ ID NO:
69)
JAAX1LREFGAX2LNAAAA;
(SEQ ID NO:
70)
JAAX1LRAFGDX2LNAA;
(SEQ ID NO:
71)
JAAX1LRAFGDX2LNAAAA;
(SEQ ID NO:
72)
JAAX1LRAFGDX2LNAE;
(SEQ ID NO:
73)
JAAX1LRAFGDX2LNAEAA;
(SEQ ID NO:
74)
JAAX1LREFGDX2LNAA;
or
(SEQ ID NO:
75)
JAAX1LREFGDX2LNAAAA,
wherein J is an electrophilic warhead;
and wherein X1 and X2 are non-natural amino acids.

101 more elements

Dependencies are inferred from the claim text.

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

Life of this patent

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

Life of this patent

Abstract

Claims24