Stabilized MAML peptides and uses thereof

1. A modified polypeptide of Formula (I),

wherein:

each R 1 and R 2 are independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;

each R 3 is independently alkyl, alkenyl, alkynyl or [R 4 —K—R 4 ] n ; each of which is substituted with 0-6 R 5 ;

each R 4 is independently alkyl, alkenyl, or alkynyl;

each R 5 is independently halo, alkyl, OR 6 , N(R 6 ) 2 , SR 6 , SOR 6 , SO 2 R 6 , CO 2 R 6 , R 6 , a fluorescent moiety, or a radioisotope;

each K is independently O, S, SO, SO 2 , CO, CO 2 , CONR 6 , or

each R 6 is independently H, alkyl, or a therapeutic agent;

n is an integer from 1-4;

x is 3, 4 or 6;

y and w are independently an integer between 0 and 15;

z is 1; and

each Xaa is independently an amino acid;

wherein the modified polypeptide consists of 8-20 contiguous amino acids of SEQ ID NO:1 and: (a) within a sequence of 8 contiguous amino acids the side chains of at least one pair of amino acids separated by 3, 4 or 6 amino acids are replaced by the linking group R 3 which connects the alpha carbons of the pair of amino acids as depicted in Formula (I); and (b) the alpha carbon of the first of the pair of amino acids is substituted with R 1 as depicted in Formula (I) and the alpha carbon of the second of the pair of amino acids is substituted with R 2 as depicted in Formula (I); wherein and N or C can be substituted by PEG, spermine, or a carbohydrate.

2. The modified polypeptide of claim 1 , wherein y is an integer from 3 to 15.

3. The modified polypeptide of claim 1 , wherein R 1 and R 2 are each independently H or C 1 -C 6 alkyl.

4. The modified polypeptide of claim 1 , wherein R 3 is a straight chain alkyl, alkenyl, or alkynyl.

5. The modified polypeptide of claim 1 wherein the sequence of [Xaa] w is LCR.

6. A compound having the formula:

wherein;

R 1 is —CH 2 CH 2 COOH [E] or —CH 2 COOH [D] or R 1 and R 8 together are R x ;

R 2 is —CH 2 CH(CH 3 ) 2 [L] or —CH 2 CH 2 CH 2 N(H)C(NH)NH 2 [R];

R 3 is —CH 2 CH 2 COOH [E]

R 4 is —CH 2 CH 2 CH 2 N(H)C(NH)NH 2 [R];

R 5 is —CH 2 CH 2 C(O)NH 2 [Q], —CH 2 CH 2 COOH [E], or CH 2 CH 2 CH 2 N(H)C(NH)NH 2 [R]; or R 5 and R 9 together are Ry; or R 5 and R 12 together are Rx;

R 6 is —CH 2 OH [S],

[H] or —CH 2 COOH [D];

R 7 is —C(OH)CH 3 [T];

R 8 is benzyl [F], —CH 2 CH(CH 3 ) 2 [L], —CH(CH 3 ) 2 [V] or R 1 and R 8 together are R x ;

R 9 is selected from: —CH 3 [A] or —CH 2 CH 2 C(O)NH 2 [Q] and —CH 2 OH [S]; or R 5 and R 9 together are R y ;

R 10 is —CH 2 CH(CH 3 ) 2 [L];

R 11 is

[H], —CH 2 CH(CH 3 ) 2 [L] or

[Y]

R 12 is —CH 2 CH 2 C(O)NH 2 [Q] and —CH 2 OH [S]; or R 5 and R 12 together are R x

provided that when R 1 and R 8 together are Rx, R 5 and R 9 are not together Ry and R 5 and R 12 are not together R x ;

further provided that when R 5 and R 9 together are Ry, R 1 and R 5 are not together R x and R 5 and R 12 are not together R x ;

further provided that when R 5 and R 12 are together R x , R 5 and R 9 are not together R y and R 1 and R 8 are not together R x ;

R x and R y are each independently alkyl, alkenyl, alkynyl; [R x1 —K—R x1 ] n ; each of which is substituted with 0-6 R x2 ;

R x1 is alkyl, alkenyl, or alkynyl;

R x2 is halo, alkyl, OR x3 , N(R x3 ) 2 , SR x3 , SOR x3 , SO 2 R x3 , CO 2 R x3 , R x3 , a fluorescent moiety, or a radioisotope;

K is O, S, SO, SO 2 , CO, CO 2 , CONR x3 , or

R x3 is H, alkyl or a therapeutic agent; and

R z and R w are independently: H, hydroxyl, an amino acid, 2 to 10 amino acids linked by peptide bonds; tat; or PEG;

n is 3, 4, or 6; and

wherein the compound binds a Notch complex with an apparent Kd of less than 1 μM as measured by surface plasmon resonance;

and wherein: a) R 1 and R 8 together are R x or b) R 5 and R 9 together are Ry; or c) R 5 and R 12 together are Rx.

7. The polypeptide of claim 6 , wherein R 1 and R 2 are each independently H or C 1 -C 6 alkyl.

8. The polypeptide of claim 6 , wherein the polypeptide is transported through the cell membrane.

9. The polypeptide of claim 1 wherein polypeptide comprises an amino acid sequence selected from SEQ ID NOs:8, 9, 10 and 11, wherein: (a) the side chains of amino acids 8 and 12 are replaced by the linking group R 3 which connects the alpha carbons of amino acids 8 and 12 as depicted in Formula (I); and (b) the alpha carbon of amino acid 8 is substituted with R 1 as depicted in Formula (I) and the alpha carbon of amino acid 12 is substituted with R 2 as depicted in Formula (I).

10. The modified polypeptide of claim 1 , wherein the MAML polypeptide consists of SEQ ID NO:8 and: (a) within a sequence of 8 contiguous amino acids the side chains of at least one pair of amino acids separated by 3, 4 or 6 amino acids are replaced by the linking group R 3 which connects the alpha carbons of the pair of amino acids as depicted in Formula (I); and (b) the alpha carbon of the first of the pair of amino acids is substituted with R 1 as depicted in Formula (I) and the alpha carbon of the second of the pair of amino acids is substituted with R 2 as depicted in Formula (I); wherein and N or C can be substituted by PEG, spermine, or a carbohydrate.

11. The modified polypeptide of claim 1 , wherein the MAML Polypeptide consists of 8-20 contiguous amino acid of SEQ ID NO:2 and: (a) within a sequence of 8 contiguous amino acids the side chains of at least one pair of amino acids separated by 3, 4 or 6 amino acids are replaced by the linking group R 3 which connects the alpha carbons of the pair of amino acids as depicted in Formula (I); and (b) the alpha carbon of the first of the pair of amino acids is substituted with R 1 as depicted in Formula (I) and the alpha carbon of the second of the pair of amino acids is substituted with R 2 as depicted in Formula (I); wherein and N or C can be substituted by PEG, spermine, or a carbohydrate.

12. A pharmaceutically acceptable salt of the modified polypeptide of Formula (I) of claim 1 .