Beta-catenin targeting peptides and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07K-007/08
C07K-014/47
C07K-001/113
A61K-038/00
출원번호
US-0825709
(2011-09-22)
등록번호
US-8957026
(2015-02-17)
국제출원번호
PCT/US2011/052755
(2011-09-22)
§371/§102 date
20130610
(20130610)
국제공개번호
WO2012/040459
(2012-03-29)
발명자
/ 주소
Verdine, Gregory L.
Grossmann, Tom N.
Yeh, Tsung-Han Johannes
출원인 / 주소
President and Fellows of Harvard College
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
19인용 특허 :
67
초록▼
The invention relates to β-catenin targeting peptides comprising an α-helical segment that are optionally stapled or stitched, and pharmaceutical compositions thereof. Uses of the inventive β-catenin targeting polypeptides including methods for treatment of disease, such as diseases associated with
The invention relates to β-catenin targeting peptides comprising an α-helical segment that are optionally stapled or stitched, and pharmaceutical compositions thereof. Uses of the inventive β-catenin targeting polypeptides including methods for treatment of disease, such as diseases associated with aberrant Wnt signaling, including cancer, are also provided.
대표청구항▼
1. A β-catenin binding polypeptide comprising an α-helical segment, wherein the polypeptide comprises the amino acid sequence: X1X2X3XL4X5Y1X6X7X8Y2X9X 10X11A 12X13X14X15, wherein X1 is selected from the group consisting of R, K and no amino acid;X2 is selected from the group consisting of R, K, W a
1. A β-catenin binding polypeptide comprising an α-helical segment, wherein the polypeptide comprises the amino acid sequence: X1X2X3XL4X5Y1X6X7X8Y2X9X 10X11A 12X13X14X15, wherein X1 is selected from the group consisting of R, K and no amino acid;X2 is selected from the group consisting of R, K, W and no amino acid;X3 is selected from the group consisting of W, Y and Q;X4 is selected from the group consisting of P, S, W, A, F and L;X5 is selected from the group consisting of E, Q, R and W;X6 is selected from the group consisting of I and L;X7 is selected from the group consisting of I and L;X8 is selected from the group consisting of D and N;X9 is selected from the group consisting of H and W;X10 is selected from the group consisting of V, W, L, M, F, and I;X11 is selected from the group consisting of Q, E, L, D, H, R, S, and V;X12 is selected from the group consisting of R, S, and K;X13 is selected from the group consisting of V, I, L, W, F and H;X14 is selected from the group consisting of M, Norleucine, I, L, W, F and H;X15 is selected from the group consisting of R, G, P, E, H, K, Q, and no amino acid; andY1 is selected from the group S, S5, R5, and Y2 is selected from the group E, S5, and R5. 2. The polypeptide of claim 1, wherein the amino acid of X1, X2, X11, X12, or X15 is a positively charged amino acid and/or the amino acid of X3, X4, X5, X6, X7, X9, X10, X13 or X14 is a bulky, hydrophobic amino acid. 3. The polypeptide of claim 1, wherein Y1 and Y2 are S5. 4. The polypeptide of claim 1 comprising a free N-terminus, an acetylated N-terminus, a linker molecule, a labeling moiety, an affinity tag, and/or a targeting moiety. 5. The polypeptide of claim 4, wherein the linker molecule is β-Ala or PEG1. 6. The polypeptide of claim 4, wherein the labeling moiety is FITC. 7. The polypeptide of claim 4, wherein the affinity tag is biotin, FLAG, 6×His, or myc. 8. The polypeptide of claim 4, wherein the targeting moiety is integrin, antibody, or antibody fragment. 9. A pharmaceutical composition comprising the polypeptide of claim 1. 10. A method of treating a cancer that exhibits Wnt-signaling dependent growth in a subject, the method comprising administering to a subject the pharmaceutical composition of claim 9 in an amount sufficient to treat the cancer. 11. A method of modulating Wnt-mediated transcription, the method comprising contacting a cell with the polypeptide of claim 1. 12. A method to inhibit cell proliferation that is dependent on aberrant Wnt-signaling, the method comprising contacting the cell with a polypeptide of claim 1. 13. A β-catenin binding polypeptide comprising an α-helical segment, wherein the polypeptide comprises the amino acid sequence: X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16, wherein X1 is selected from the group consisting of R, V, E, Q, T, K, W, and L;X2 is selected from the group consisting of W, S, L, N, Y, K, V, and Q:X3 is selected from the group consisting of P, L, S, W, A, and F;X4 is selected from the group consisting of E, Q, and W;X5 isS;X6 is I;X7 is L;X8 is D;X9 is selected from the group consisting of E and Q;X10 is H;X11 is selected from the group consisting of W, V, F, M, L, and I;X12 is selected from the group consisting of E, Q, H, D, V, and L;X13 is selected from the group consisting of R and K;X14 is selected from the group consisting of V and W;X15 is selected from the group consisting of M, W, F, and E; andX16 is selected from the group consisting of R, G, P, E, and Q, with the proviso that the sequence is not the wild-type sequence from Axin. 14. The polypeptide of claim 13, wherein X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16 is modified to induce and/or stabilize an α-helical conformation. 15. The polypeptide of claim 14, wherein the amino acids positioned at i, i+4 and/or i, i+7 are cross-linked by a hydrocarbon cross-link. 16. The polypeptide of claim 14, wherein the modification is selected from the group consisting of a peptide staple, a lactam cross-link, a disulfide cross-link, α-methylation, N-caps, and a hydrogen bond surrogate. 17. The polypeptide of claim 16, wherein the modification is a peptide staple. 18. The polypeptide of claim 17, wherein the amino acids positioned at i, i+4 and/or i, i+7 are stapled. 19. The polypeptide of claim 13, wherein the sequence is not ENPESILDEHVQRVMR (SEQ ID NO: 1) (amino acids 469-484 of rat axin). 20. A β-catenin binding polypeptide comprising an amino acid sequence of any one of SEQ ID NOs.: 28-58. 21. An isolated polypeptide comprising an α-helical segment, wherein the peptide binds β-catenin and comprises an amino acid sequence selected form the group consisting of the sequences: ENPES5ILDS5HVQRVM (SEQ ID NO:14), PES5ILDS5HVQRVM (SEQ ID NO:15), PES5ILDS5HVRRVMR (SEQ ID NO:16), PQS5ILDS5HVRRVMR (SEQ ID NO:17), PQS5ILDS5HVRRWMR (SEQ ID NO:18), PQS5ILDS5HVRRVWR (SEQ ID NO:19), RWPQS5ILDS5HVRRVWR (SEQ ID NO:20), RRWPQS5ILDS5HVRRVWR (SEQ ID NO:21), RWPRS5ILDS5HVRRVWR (SEQ ID NO:22), RRWPRS5ILDS5HVRRVWR (SEQ ID NO:23), RWPQS5ILDS5HVRRWNleR (SEQ ID NO:24), RWPRS5ILDS5HVRRWNleR (SEQ ID NO:25), RWPQS5ILDS5HVRRRWR (SEQ ID NO:26), RWPRS5ILDS5HVRRRWR (SEQ ID NO:27).
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