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 method of treating a subject having a disorder with reduced p53 activity, comprising administering to the subject having the disorder a therapeutically effective amount of a peptide of Formula (I),
or pharmaceutically acceptable salt thereof,
wherein:
each R 1 and R 2 is 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 independently substituted with 0-6 R 5 ;
each R 4 and R 4 ′ is 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;
each x is independently 6;
each y is independently an integer from 0-100;
each w is independently an integer from 0-100;
z is an integer from 1-10; and
each Xaa is independently an amino acid,
wherein the peptide comprises a span of 8 contiguous amino acid residues that comprises Phe, Leu, and Trp, wherein the peptide exhibits a binding affinity for HDM2 that is from about 0.75 nM to about 110 nM.
2. The method of claim 1 , wherein the peptide binds to HDM2.
3. The method of claim 1 , wherein each R 3 is independently an alkenylene group.
4. The method of claim 1 , wherein each R 3 is independently an alkylene group.
5. The method of claim 1 , wherein each R 1 and each R 2 is independently alkyl.
6. The method of claim 1 , wherein each R 1 and each R 2 is independently methyl.
7. The method of claim 1 , wherein each R 1 and each R 2 is independently H.
8. The method of claim 1 , wherein z is 1.
9. The method of claim 1 , wherein each w is independently an integer from 3 to 15.
10. The method of claim 1 , wherein each y is independently an integer from 3 to 15.
11. The method of claim 1 , wherein the peptide is permeable to a cell membrane.
12. The method of claim 1 , wherein the peptide comprises a helix.
13. The method of claim 1 , wherein the peptide comprises an α-helix.
14. The method of claim 1 , wherein R 3 extends across one helical turn.
15. The method of claim 1 , wherein R 3 extends across two helical turns.
16. The method of claim 1 , wherein the disorder is a cancer selected from the group consisting of osteosarcoma, colon cancer, breast cancer, T-cell cancer, B-cell cancer, mucoepidermoid carcinoma, retinoblastoma, lymphoma, leukemia, myeloma, and medulloblastoma.
17. A method for preparing a peptide of Formula (I),
or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 and R 2 is 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 independently substituted with 0-6 R 5 ;
each R 4 and R 4 ′ is 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;
each x is independently 6;
each y is independently an integer from 0-100;
each w is independently an integer from 0-100;
z is an integer from 1-10; and
each Xaa is independently an amino acid,
wherein the peptide comprises a span of 8 contiguous amino acid residues that comprises Phe, Leu, and Trp, wherein the peptide exhibits a binding affinity for HDM2 that is from about 0.75 nM to about 110 nM; the method comprising:
(a) synthesizing a peptide or a pharmaceutically acceptable salt thereof using solid phase peptide chemistry, wherein the synthesized peptide or pharmaceutically acceptable salt thereof comprises at least two moieties capable of undergoing a metathesis reaction; and
(b) performing a ring-closing metathesis reaction;
wherein the peptide of Formula (I) or the pharmaceutically acceptable salt thereof is produced.