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.
대표청구항▼
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 R1 and R2 is independently H, alkyl, al
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 R1 and R2 is independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;each R3 is independently alkylene, alkenylene, alkynylene, or [R4—K—R4′]n, each of which is independently substituted with 0-6 R5;each R4 and R4′ is independently alkylene, alkenylene or alkynylene;each R5 is independently halo, alkyl, OR6, N(R6)2, SR6, SOR6, SO2R6, CO2R6, R6, a fluorescent moiety, or a radioisotope;each K is independently O, S, SO, SO2, CO, CO2, CONR6, or each R6 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; andeach 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 R3 is independently an alkenylene group. 4. The method of claim 1, wherein each R3 is independently an alkylene group. 5. The method of claim 1, wherein each R1 and each R2 is independently alkyl. 6. The method of claim 1, wherein each R1 and each R2 is independently methyl. 7. The method of claim 1, wherein each R1 and each R2 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 R3 extends across one helical turn. 15. The method of claim 1, wherein R3 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 R1 and R2 is independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;each R3 is independently alkylene, alkenylene, alkynylene, or [R4—K—R4′]n, each of which is independently substituted with 0-6 R5;each R4 and R4′ is independently alkylene, alkenylene or alkynylene;each R5 is independently halo, alkyl, OR6, N(R6)2, SR6, SOR6, SO2R6, CO2R6, R6, a fluorescent moiety, or a radioisotope;each K is independently O, S, SO, SO2, CO, CO2, CONR6, or each R6 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; andeach 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.
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