Selective Mcl-1 binding peptides

1. A compound comprising an internally cross-linked polypeptide comprising the amino acid sequence:

(SEQ ID NO: 1)

F1 G1 A2 B2 C2 D2 E2 F2 G2 A3 B3 C3 D3 E3 F3 G3 A4

B4 C4 D4 E4 F4 G4 A5,

wherein:

F1 is R or is missing;

G1 is P or is missing;

A2 is E or is missing;

B2 is I;

C2 is W;

D2 is M, L, F, I, or norleuicine (Nle);

E2 is T, A, V, or Aib;

F2 is Q, or R;

G2 is G, H, E, or S;

A3 is L, or I;

B3 is R, D, Q, Aib, or Me-Leu;

C3 is R;

D3 is L, or I;

E3 is G;

F3 is D;

G3 is E;

A4 is I, V, or F;

B4 is N;

C4 is A;

D4 is Y or R;

E4 is Y;

F4 is A or is missing;

G4 is R or is missing;

A5 is R or is missing; and

the side chains of two amino acids separated by two, three or six amino acids are replaced by an internal cross-link; the side chains of three amino acids are replaced by an internal stitch; the side chains of four amino acids are replaced by internal cross-links or internal stitches,; or the side chains of at least four amino acids are replaced by internal cross-links, internal stitches, or a combination of internal cross-links and stitches,

wherein the cross-link is between the alpha carbons of: E2 and B3; F2 and C3; or B4 and F4.

2. The compound of claim 1 wherein the side chains of two amino acids separated by 3 or 6 amino acids are replaced by an internal cross-link.

3. The compound of claim 2 wherein the internal cross-link is an alkylene or alkenylene group.

4. The compound of claim 3 wherein the alkylene or alkenylene is a C7, C8, C9, C10, C11, C12 or C13 alkylene or alkenylene.

5. A compound comprising a polypeptide having a sequence selected from the group consisting of:

(SEQ ID NO: 2)

RPEIWMTQGLRRLGDEINAYYAR,

(M1; SEQ ID NO: 6)

IWNleTQGLRRLGDEINAYYARR,

and

(B1; SEQ ID NO: 23)

IWFAQEIDRIGDEVNAYYARR ;

wherein: none or one, of the amino acids are replaced by another amino acid, and the side chains of two amino acids are replaced by an internal crosslink,

wherein the cross-link is between the alpha carbons of: E2 and B3; F2 and C3; or B4 and F4.

6. The compound of claim 1 comprising a peptide selected from:

(SEQ ID NO: 3)

RPEIWMXQGLXRLGDEINAYYA;

(SEQ ID NO: 4)

RPEIWMTQGLRXLGDXINAYYA;

(SEQ ID NO: 5)

RPEIWMTQGLRRLGDEINAYYR;

(SEQ ID NO: 20)

EIWMXQGLXRLGDEINAYYA;

(SEQ ID NO: 21)

PEIWMTQGLRXLGDXINAYYA;

(SEQ ID NO: 22)

PEIWMTQGLRRLGDEINAYYR;

(SEQ ID NO: 6)

IWNleTQGLRRLGDEINAYYARR;

(SEQ ID NO: 7)

IWNleTQGLRXLGDXINAYYARR;

(SEQ ID NO: 8)

IWNleTQGLRRLGDEIXAYYXRR;

(SEQ ID NO: 9)

IWNleXQGLXRLGDEINAYYARR;

(SEQ ID NO: 10)

IWNleXQGLXRLGDEINAYYAR;

(SEQ ID NO: 11)

EIWNleXQGLXRLGDEINAYYAR;

(SEQ ID NO: 12)

EIWNleXQGLXRLGDEINAYYA;

(SEQ ID NO: 13)

IWNleXQELXRLGDEINAYYARR;

(SEQ ID NO: 14)

IWNleXQSLXRLGDEINAYYARR;

(SEQ ID NO: 15)

IWNleXQSLXRLGDEINAYYAR;

(SEQ ID NO: 16)

IWNleXQEDCRLGDEINAYYAR;

(SEQ ID NO: 17)

IWNleXQGLXRLGDEINARYAR;

(SEQ ID NO: 18)

IWNleXQEDCRLGDEINARYAR;

(SEQ ID NO: 19)

IWNleXRGLXRLGDEINAYYAR;

(SEQ ID NO: 23)

IWFAQEIDRIGDEVNAYYARR;

(SEQ ID NO: 24)

IWFAQEIDXIGDXVNAYYARR;

(SEQ ID NO: 25)

IWFAQEIDRIGDEVXAYYXRR;

(SEQ ID NO: 26)

IWFXQEIXRIGDEVNAYYARR;

(SEQ ID NO: 27)

IWFXQEIXRIGDEVNAYYAR;

(SEQ ID NO: 28)

EIWFXQEIXRIGDEVNAYYAR;

(SEQ ID NO: 29)

IWFAXEIDXIGDEVNAYYARR;

and

(SEQ ID NO: 30)

XWFAQEIXRIGDEVNAYYARR;

and

wherein X represents an amino acid whose side chain has been replaced by an internal cross-link.

7. The compound of claim 1 the cross-link is a C8 alkylene or a C11 alkylene.

8. The compound of claim 1 , wherein A3 is L, D3 is L, E3 is G, F3 is D, and A4 is I or V.

9. The compound of claim 8 , wherein the amino acid sequence of the peptide comprises IWNleXQELXRLGDEINARYAR (SEQ ID NO:18), and wherein X represents an amino acid whose side chain has been replaced by an internal cross-link.

10. The compound of claim 1 , wherein A3 is L, D3 is I, E3 is G, F3 is D, and A4 is I.

11. The compound of claim 1 , wherein A3 is I, D3 is L, E3 is G, F3 is D, and A4 is I.

12. The compound of claim 1 , wherein A3 is I, D3 is isoleucine, E3 is G, F3 is D, and A4 is I.

13. The compound of claim 1 , wherein the amino acid sequence of the peptide comprises a sequence selected from the group consisting of:

(SEQ ID NO: 31)

IWFAQEIDRIGDEVNAYYAR.

(SEQ ID NO: 32)

EIWFAQEIDRIGDEVNAYYAR,

(SEQ ID NO: 33)

RPEIWLTQSLQRLGDEINAYYAR,

(SEQ ID NO: 34)

RPEIWLTQHLQRLGDEINAYYAR ,

(SEQ ID NO: 44)

RPEIWITQELRRIGDEINAYYAR,

(SEQ ID NO: 45)

IWMTQGLRRLGDEINAYYAR,

(SEQ ID NO: 53)

RPEIWNleTQGLRRLGDEINAYYAR,

and

(SEQ ID NO: 54)

IWMTQGLRRLGDEINAYYARR.

14. The compound of claim 1 , wherein the amino acid sequence of the peptide comprises a sequence selected from the group consisting of:

(SEQ ID NO: 46)

IXNleTQXIRRLGDEINAYYARR,

(SEQ ID NO: 47)

IWXTQGXRRLGDEINAYYARR,

(SEQ ID NO: 48)

IWNleTQXLRRXGDEINAYYARR,

(SEQ ID NO: 49)

IWNleTQGXRRLXDEINAYYARR,

(SEQ ID NO: 50)

IWNleTQGLXRLGXEINAYYARR,

(SEQ ID NO: 51)

IWNleTQGLRRLXDEIXAYYARR,

and

(SEQ ID NO: 52)

IWNleTQGLRRLGDXINAXYARR;

and wherein X represents an amino acid side chain has been replaced by an internal cross-link.

15. A pharmaceutical composition comprising the compound of claim 1 .

16. The compound of claim 6 , wherein the amino acid sequence of the peptide comprises IWNleXQSLXRLGDEINAYYARR (SEQ ID NO:14), wherein X represents an amino acid whose side chain has been replaced by an internal cross-link.