최소 단어 이상 선택하여야 합니다.
최대 10 단어까지만 선택 가능합니다.
다음과 같은 기능을 한번의 로그인으로 사용 할 수 있습니다.
NTIS 바로가기다음과 같은 기능을 한번의 로그인으로 사용 할 수 있습니다.
DataON 바로가기다음과 같은 기능을 한번의 로그인으로 사용 할 수 있습니다.
Edison 바로가기다음과 같은 기능을 한번의 로그인으로 사용 할 수 있습니다.
Kafe 바로가기국가/구분 | United States(US) Patent 등록 |
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국제특허분류(IPC7판) |
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출원번호 | US-0608641 (2015-01-29) |
등록번호 | US-10227380 (2019-03-12) |
발명자 / 주소 |
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출원인 / 주소 |
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대리인 / 주소 |
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인용정보 | 피인용 횟수 : 0 인용 특허 : 290 |
Provided herein are peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.
1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least 60% identical to SEQ ID NO. 448, wherein the peptidomimetic macrocycle has the formula: or a pharmaceutically acceptable salt thereof, wherein:each A, C, D, and E is independently an amino acid;each B is independently
1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least 60% identical to SEQ ID NO. 448, wherein the peptidomimetic macrocycle has the formula: or a pharmaceutically acceptable salt thereof, wherein:each A, C, D, and E is independently an amino acid;each B is independently an amino acid, [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;or at least one of R1 and R2 forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids; each L and L′ is independently a macrocycle-forming linker of formula each L1, L2 and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R4-K—R4-]n, each being optionally substituted with R5;each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;each K is independently O, S, SO, SO2, CO, CO2, or CONR3;each R5 is independently halogen,alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;each R7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;each R8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;each v and w is independently an integer from 1-1000,u is an integer from 1-10;each x, y and z is independently an integer from 0-10; andeach n is independently an integer from 1-5. 2. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which has improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 3. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which has a reduced ratio of binding affinities to MDMX versus MDM2 relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 4. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which has improved in vitro anti-tumor efficacy against p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 5. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which shows improved in vitro induction of apoptosis in p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 6. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which has an improved in vitro anti-tumor efficacy ratio for p53 positive versus p53 negative or mutant tumor cell lines relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 7. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which has improved in vivo anti-tumor efficacy against p53 positive tumors relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 8. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which has improved in vivo induction of apoptosis in p53 positive tumors relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 9. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which has improved cell permeability relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 10. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, which has improved solubility relative to a corresponding peptidomimetic macrocycle with a w of 0, 1 or 2. 11. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 3, wherein each E is independently an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine). 12. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 1, wherein [D]v, is -Leu1-Thr2-Phe3. 13. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 1, wherein w is 3. 14. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 1, wherein w is 3-6. 15. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 1, wherein v is 1-10. 16. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 15, wherein v is 3. 17. The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1, comprising at least one amino acid which is an amino acid analog. 18. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 1, wherein x+y+z is 2, 3, or 6. 19. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 80% identical to an amino acid sequence of SEQ ID NO. 448. 20. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 90% identical to an amino acid sequence of SEQ ID NO. 448. 21. The peptidomimetic macrocycle or the pharmaceutically acceptable salt of claim 1, wherein each R1 and R2 is a methyl. 22. A method of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1. 23. A method of modulating the activity of p53 and/or MDM2 and/or MDMX in a subject comprising administering to the subject a peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1. 24. A method of antagonizing the interaction between p53 and MDM2 and/or between p53 and MDMX proteins in a subject comprising administering to the subject a peptidomimetic macrocycle or pharmaceutically acceptable salt thereof of claim 1.
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