Stabilized p53 peptides and uses thereof
Cross-linked peptides related to human p53 and bind to HMD2 or a family member of HDM2 useful for promoting apoptosis, e.g., in the treatment of and identifying therapeutic agents that binding to HMD2 or a family member of HDM2.
1. A modified polypeptide of Formula (I)
or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 and R 2 are independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;
each R 3 is independently alkylene, alkenylene, alkynylene, or [R 4 —K—R 4 ′] n , each of which is substituted with 0-6 R 5 ;
each R 4 and R 4 ′ are independently alkylene, alkenylene, or alkynylene;
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;
each n is independently an integer from 1-4;
x is 6;
each y is independently an integer from 1-15;
each w is independently an integer from 3 to 15;
z is an integer from 1-10; and
each Xaa is independently an amino acid;
wherein the modified polypeptide or the pharmaceutically acceptable salt thereof comprises at least 8 contiguous amino acids of Leu 1 Ser 2 Gln 3 Glu 4 Thr 5 Phe 6 Ser 7 Asp 8 Leu 9 Trp 10 Lys 11 Leu 12 Leu 13 Pro 14 Glu 15 Asn 16 (SEQ ID NO:2), wherein the side chains of Ser 7 and Pro 14 are replaced by the linking group R 3 , and none or up to 6 amino acids other than Phe 6 , Trp 10 and Leu 13 are independently replaced by any other amino acid.
2. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein the modified polypeptide or the pharmaceutically acceptable salt thereof binds to HDM2.
3. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein each R 3 is independently an alkenylene containing a single double bond, and both R 1 and R 2 are H.
4. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein the modified polypeptide or the pharmaceutically acceptable salt thereof does not have a net negative charge at pH 7.
5. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 4 , wherein the modified polypeptide or the pharmaceutically acceptable salt thereof comprises at least one amino acid that has a positive charge at pH 7, wherein the at least one amino acid is at either: (a) amino terminal to Leu 1 or the amino acid substituted for Leu 1 or (b) carboxy terminal to Asn 16 or the amino acid substituted for Asn 16 .
6. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 and R 2 are each independently H or C 1 -C 6 alkyl.
7. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein each R 3 is independently C 8 alkylene.
8. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein each R 3 is independently C 11 alkylene.
9. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein each R 3 is independently alkenylene.
10. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein each R 3 is independently C 8 alkenylene.
11. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein each R 3 is independently C 11 alkenylene.
12. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein each R 3 is independently a straight chain alkylene, alkenylene, or alkynylene.
13. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , further comprising a copolymer of lactic and glycolic acid.
14. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , further comprising an amino-terminal fatty acid.
15. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , further comprising a biotin moiety.
16. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein the modified polypeptide or the pharmaceutically acceptable salt thereof is capable of being transported through a cell membrane.
17. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , further comprising a PEG, a tat protein, an affinity label, a targeting moiety, a fatty acid-derived acyl group, a biotin moiety, or a fluorescent probe.
18. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 17 , wherein the fluorescent probe is fluorescein or rhodamine.
19. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 17 , wherein the fluorescent probe is linked via a thiocarbamate or carbamate linkage to the modified polypeptide or the pharmaceutically acceptable salt thereof.
20. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein each R 1 and R 2 are independently C 1 -C 3 alkyl.
21. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein both R 1 and R 2 are methyl.
22. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , further comprising a targeting moiety.
23. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein the modified polypeptide or the pharmaceutically acceptable salt thereof binds to HDMX.
24. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , wherein the modified polypeptide or the pharmaceutically acceptable salt thereof binds to HDMX and HDM2.
25. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1 , 2 , 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 20 , 21 , 23 or 24 , wherein z is 1.