Stabilized p53 peptides and uses thereof

A compound having the formula:

• R1 is the side chain of any amino acid other than Gln;
• R2 is —CH2OH [S];
• R3 is —CH2CH2C(O)NH2 [Q]
• R4 is the side chain of any amino acid other than Glu or Asp;
• R5 is —C(OH)CH3 [T];
• R6 is benzyl [F]
• R7 and R14 together are Rx;
• R8 is R4 is the side chain of any amino acid other than Glu or Asp;
• R9 is —CH2CH(CH3)2 [L];
• R10 is;
• R11 is the side chain of any amino acid other than Lys;
• R12 and R13 are —CH2CH(CH3)2 [L];
• R15 is —CH2CH2C(O)NH2 [Q];
• and
• R16 is —CH2C(O)NH2 [N].
• Rx is alkyl, alkenyl, alkynyl;
• [Rx1—K—Rx1]n;
• each of which is substituted with 0-6 Rx2;
• Rx1 and Rx1′ are independently alkyl, alkenyl, or alkynyl;
• Rx2 is halo, alkyl, ORx3, N(Rx3)2, SRx3, SORx3, SO2Rx3, CO2Rx3, Rx3, a fluorescent moiety, or a radioisotope;
• K is O, S, SO, SO2, CO, CO2, CONRx3, or
• R13 is H, alkyl or a therapeutic agent;
• and
• Rz and Rw are independently:
• H, hydroxyl, amide (NH2), an amino acid, 2 to 10 amino acids linked by peptide bonds;
• tat;
• and PEG.

A modified polypeptide of Formula (II),

• or a pharmaceutically acceptable salt thereof,
• wherein;
• each R1 and R2 are independently H or a C1 to C10 alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;
• R3 is alkylene, alkenylene or alkynylene, or [R4′-K-R4]n;
• each of which is substituted with 0-6 R5;
• R4 and R4′ are independently alkylene, alkenylene or alkynylene (e.g., each are independently a C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkylene, alkenylene or alkynylene);
• R5 is halo, alkyl, OR6, N(R6)2, SR6, SOR6, SO2R6, CO2R6, R6, a fluorescent moiety, or a radioisotope;
• K is O, S, SO, SO2, CO, CO2, CONR6, or
• aziridine, episulfide, diol, amino alcohol;
• R6 is H, alkyl, or a therapeutic agent;
• n is 2, 3, 4 or 6;
• x is an integer from 2-10;
• w and y are independently an integer from 0-100;
• z is an integer from 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10);
• and
• each Xaa is independently an amino acid (e.g., one of the 20 naturally occurring amino acids or any naturally occurring non-naturally occurring amino acid);
• R7 is PEG, a tat protein, an affinity label, a targeting moiety, a fatty acid-derived acyl group, a biotin moiety, a fluorescent probe (e.g. fluorescein or rhodamine) linked via, e.g., a thiocarbamate or carbamate linkage;
• R8 is H, OH, NH2, NHR8a, NR8aR8b;
• wherein the polypeptide comprises at least 8 contiguous amino acids of SEQ ID NO:1 (human p53) or a variant thereof, SEQ ID NO:2 or a variant thereof, or another polypeptide sequence described herein except that:
• (a) within the 8 contiguous amino acids of SEQ ID NO:1 the side chains of at least one pair of amino acids separated by 3, 4 or 6 amino acids is replaced by the linking group, R3, 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 R1 as depicted in Formula II and the alpha carbon of the second of the pair of amino acids is substituted with R2 as depicted in Formula II.