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 modified polypeptide of Formula (I) or a pharmaceutically acceptable salt thereof,wherein:each R1 and R2 are independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;each R3 is independently alkylene, alkenylene, alkynylene, or [R4—K—R4′]n, eac
1. A modified polypeptide of Formula (I) or a pharmaceutically acceptable salt thereof,wherein:each R1 and R2 are 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 substituted with 0-6 R5;each R4 and R4′ are 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;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; andeach Xaa is independently an amino acid;wherein the modified polypeptide or the pharmaceutically acceptable salt thereof comprises at least 8 contiguous amino acids of Leu1 Ser2 Gln3 Glu4 Thr5 Phe6 Ser7 Asp8 Leu9 Trp10 Lys11 Leu12 Leu13 Pro14 Glu15 Asn16 (SEQ ID NO:2), wherein the side chains of Ser7 and Pro14 are replaced by the linking group R3, and none or up to 6 amino acids other than Phe6, Trp10 and Leu13 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 R3 is independently an alkenylene containing a single double bond, and both R1 and R2 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 Leu1 or the amino acid substituted for Leu1 or (b) carboxy terminal to Asn16 or the amino acid substituted for Asn16. 6. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein R1 and R2 are each independently H or C1-C6 alkyl. 7. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R3 is independently C8 alkylene. 8. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R3 is independently C11 alkylene. 9. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R3 is independently alkenylene. 10. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R3 is independently C8 alkenylene. 11. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R3 is independently C11 alkenylene. 12. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R3 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 R1 and R2 are independently C1-C3 alkyl. 21. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein both R1 and R2 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.
Hubbard Vance M. (Bedford) Brunson Welton K. (Bedford) Saied V. C. (Wichita Falls TX), Apparatus and method for raising a skin wheal and anesthetizing skin.
Braisted Andrew C. ; Judice J. Kevin ; McDowell Robert S. ; Phelan J. Christopher ; Starovasnik Melissa A. ; Wells James A., Constrained helical peptides and methods of making same.
Borchardt Ronald T. (Lawrence KS) Siahaan Teruna (Lawrence KS) Gangwar Sanjeev (Lawrence KS) Stella Valentino J. (Lawrence KS) Wang Binghe (Norman OK), Cyclic prodrugs of peptides and peptide nucleic acids having improved metabolic stability and cell membrane permeability.
Bohme Ekkehard H. (Cincinnati OH) Gerhart Fritz (Kehl Leutesheim DEX) Higgins William (Strasbourg FRX), Derivatives of 2,6-diamino-3-haloheptanedioic acid.
Lane,David Philip; B철ttger,Volker; B철ttger,Angelika; Picksley,Steven Michael; Hochkeppel,Heinz Kurt; Garcia Echeverria,Carlos; Ch챔ne,Patrick; Furet,Pascal, Inhibitors of the interaction between P53 and MDM2.
Lilley Stephen J. (Sawston GBX) Taylor Hugh F. (Sawston GBX) Theobald David R. (Huntingdon GBX) Carlson Craig J. (Andover MA) Rosen David I. (Arlington MA) Johnson Thomas R. (Milford NH), Medical injection system and method, gas spring thereof and launching device using gas spring.
Bartkovitz, David Joseph; Chu, Xin-Jie; Liu, Jin-Jun; Morgan Ross, Tina; Zhang, Zhuming, N-substituted-pyrrolidines as inhibitors of MDM2-P-53 interactions.
McKinnon ; Jr. Charles N. (Laguna Niguel CA) Peterson Steven F. (West Linn OR) Smith Paul E. (Tualatin OR) Nakagawa Takaaki (Tigard OR) Bartholomew Victor L. (Tigard OR), Needleless hypodermic injection device.
Peterson Steven F. (West Linn OR) McKinnon ; Jr. Charles N. (Laguna Niguel CA) Smith Paul E. (Tualatin OR) Nakagawa Takaaki (Tigard OR) Bartholomew Victor L. (Tigard OR), Needleless hypodermic injection methods and device.
Grubbs Robert H. ; Miller Scott J. ; Blackwell Helen E., Synthesis of conformationally restricted amino acids, peptides, and peptidomimetics by catalytic ring closing metathesis.
Nash, Huw M.; Annis, David Allen; Kapeller-Libermann, Rosana; Sawyer, Tomi K.; Kawahata, Noriyuki, Peptidomimetic macrocycles with improved properties.
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