IP Library › Granted Patent US 12,534,501
Granted Patent B2
US 12,534,501 · App. 17/455,831 · Granted Jan 27, 2026

Targeting deregulated Wnt signaling in cancer using stabilized alpha-helices of BCL-9

Inventors: Loren D. Walensky (Newton, MA); Ruben Carrasco (Brookline, MA); Gregory H. Bird (Pelham, NH)
Assignee: Dana-Farber Cancer Institute, Inc.
C07K14/47A61K38/1709A61K45/06C07K14/82G01N33/53A61K38/00
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Quick Facts
Patent No.
US 12,534,501
App. No.
17/455,831
Granted
Jan 27, 2026
Kind
B2
Abstract

The invention provides structurally-constrained peptides by hydrocarbon stapling of a BCL9 HD2 helix for use as a therapeutic agent. The invention further provides methods and kits for use of the structurally-constrained peptide of the instant invention. The invention is based, at least in part, on the results provided herein demonstrating that hydrocarbon stapled helical peptides display excellent proteolytic, acid, and thermal stability, restore the native helical structure of the peptide, possess superior pharmacokinetic properties compared to the corresponding unmodified peptides, and are highly effective in binding to β-catenin in vitro, in cellulo, and in vivo, disrupting the BCL9/β-catenin interaction, and thereby interfering with deregulated Wnt/β-catenin signaling for therapeutic benefit in a variety of human diseases including human cancer.

Claims (275)

1 . A pharmaceutical composition comprising:

a structurally constrained peptide comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 2 with at least one hydrocarbon staple, wherein the at least one hydrocarbon staple links the side chain of a first non-natural amino acid that replaces a first BCL9-HD2 amino acid selected from the group consisting of Leu-351, Ser-352, Gln-353, Glu-354, Gln-355, His-358, Arg-359, Arg-361, Ser-362, Leu-363, Thr-365, Leu-366, Ile-369, Gln-370, Met-372, Leu-373, and Phe-374 with the side chain of a second non-natural amino acid that replaces a second different BCL9-HD2 amino acid selected from the group consisting of Leu-351, Ser-352, Gln-353, Glu-354, Gln-355, Leu-356, Glu-357, His-358, Arg-359, Glu-360, Arg-361, Ser-362, Leu-363, Thr-365, Leu-366, Arg-367, Asp-368, Ile-369, Gln-370, Arg-371, Met-372, Leu-373, and Phe-374; wherein the structurally constrained peptide inhibits the interaction between β-catenin and BCL9;

an additional therapeutic agent; and

a pharmaceutically acceptable carrier.

2 . The pharmaceutical composition of claim 1 , wherein the additional therapeutic agent is an anti-cancer compound or an angiogenesis inhibitor.

3 . The pharmaceutical composition of claim 1 , wherein the additional therapeutic agent is 5-fluorouracil or doxorubicin.

4 . The pharmaceutical composition of claim 1 , wherein the structurally constrained peptide and the additional therapeutic agent are linked together.

5 . The pharmaceutical composition of claim 1 , wherein the structurally constrained peptide comprises an interacting face comprised of amino acids that interact with B-catenin, wherein the interacting face comprises BCL9 residues Gln-355, His-358, Arg-359, Ser-362, Leu-363, Leu-366, Ile-369, Gln-370, Leu-373, and Phe-374.

6 . The pharmaceutical composition of claim 5 , wherein the interacting face represents a single face of an α-helix.

7 . The pharmaceutical composition of claim 6 , wherein the single face of a helix comprises one, two, three, or four adjacent stacked columns of amino acids, wherein the stacked columns of amino acids are defined by positions a, d, and g; positions b and e; or positions c and f; in an alpha helix having 3.6 amino acids per turn wherein the amino acids are consecutively and serially assigned positions a-g; and positions a and d; positions b and e; or positions c and f in a 3 10 helix having 3 amino acids per turn wherein the amino acids are consecutively and serially assigned positions a-f; or homologues thereof.

8 . The pharmaceutical composition of claim 1 , wherein the at least one hydrocarbon staple is formed by an olefin metathesis reaction.

9 . The pharmaceutical composition of claim 1 , wherein the first and second non-natural amino acids are selected from the following:

10 . The pharmaceutical composition of claim 1 , wherein the structurally constrained peptide comprises 1 to 2 staples within the BCL9 HD2 peptide.

11 . The pharmaceutical composition of claim 1 , wherein the structurally constrained peptide of BCL9-HD2 comprises two hydrocarbon staples and the two hydrocarbon staples link the positions designated as X within any one of the following BCL9 HD2 stapled peptides:

i, i + 3 double staples:

(SEQ ID NO: 65)

X SQ X QLEHRERSLQTLRDIQ X BL X;

(SEQ ID NO: 66)

X SQ X QLEHRERSLQTLRDI X RB X F;

or

(SEQ ID NO: 67)

X SQ X QLEHRERSLQTLRD X QRB X F;

i, i + 4 double staples:

(SEQ ID NO: 68)

X SQE X LEHRERSLQTLRDI X RBL X;

(SEQ ID NO: 69)

X SQE X LEHRERSLQTLRD X QRB X F;

or

(SEQ ID NO: 70)

X SQE X LEHRERSLQTL X DIQR X LF;

i, i + double staples:

(SEQ ID NO: 71)

X SQEQLE X RERSLQTL X DIQRBL X;

(SEQ ID NO: 72)

X SQEQLE X RERSLQT X RDIQRB X F;

(SEQ ID NO: 73)

X SQEQLE X RERSLQ X LRDIQR X LF.

wherein B is norleucine.

12 . The pharmaceutical composition of claim 1 , wherein the structurally constrained peptide comprises the amino acid sequence of:

SAH-BCL9 C :

(SEQ ID NO: 5)

LSQEQLEHRE X SLQ X LRDIQRBLF,

wherein X is a staple position, and wherein B is norleucine.

13 . The pharmaceutical composition of claim 1 , wherein the one or more additional therapeutic agents is a second structurally constrained peptide.

14 . A pharmaceutical composition comprising a BCL9 HD2 stapled peptide, wherein a hydrocarbon staple links the staple positions designated as X in any one of the following BCL9 HD2 stapled peptides:

i, i + 4 single staples:

(SEQ ID NO: 8)

X SQE X LEHRERSLQTLRDIQRBLF;

(SEQ ID NO: 9)

L X QEQ X EHRERSLQTLRDIQRBLF;

(SEQ ID NO: 10)

LS X EQL X HRERSLQTLRDIQRBLF;

(SEQ ID NO: 11)

LSQ X QLE X RERSLQTLRDIQRBLF;

(SEQ ID NO: 12)

LSQE X LEH X ERSLQTLRDIQRBLF;

(SEQ ID NO: 13)

LSQEQ X EHR X RSLQTLRDIQRBLF;

(SEQ ID NO: 14)

LSQEQL X HRE X SLQTLRDIQRBLF;

(SEQ ID NO: 15)

LSQEQLE X RER X LQTLRDIQRBLF;

(SEQ ID NO: 16)

LSQEQLEH X ERS X QTLRDIQRBLF;

(SEQ ID NO: 17)

LSQEQLEHR X RSL X TLRDIQRBLF;

(SEQ ID NO: 18)

LSQEQLEHRE X SLQ X LRDIQRBLF;

(SEQ ID NO: 19)

LSQEQLEHRER X LQT X RDIQRBLF;

(SEQ ID NO: 20)

LSQEQLEHRERS X QTL X DIQRBLF;

(SEQ ID NO: 21)

LSQEQLEHRERSL X TLR X IQRBLF;

(SEQ ID NO: 22)

LSQEQLEHRERSLQ X LRD X QRBLF;

(SEQ ID NO: 23)

LSQEQLEHRERSLQT X RDI X RBLF;

(SEQ ID NO: 24)

LSQEQLEHRERSLQTL X DIQ X BLF;

(SEQ ID NO: 25)

LSQEQLEHRERSLQTLR X IQR X LF;

(SEQ ID NO: 26)

LSQEQLEHRERSLQTLRD X QRB X F;

or

(SEQ ID NO: 27)

LSQEQLEHRERSLQTLRDI X RBL X ;

i, i + 7 staples:

(SEQ ID NO: 28)

X SQEQLE X RERSLQTLRDIQRBLF;

(SEQ ID NO: 29)

L X QEQLEH X ERSLQTLRDIQRBLF;

(SEQ ID NO: 30)

LS X EQLEHR X RSLQTLRDIQRBLF;

(SEQ ID NO: 31)

LSQ X QLEHRE X SLQTLRDIQRBLF;

(SEQ ID NO: 32)

LSQE X LEHRER X LQTLRDIQRBLF;

(SEQ ID NO: 33)

LSQEQ X EHRERS X QTLRDIQRBLF;

(SEQ ID NO: 34)

LSQEQL X HRERSL X TLRDIQRBLF;

(SEQ ID NO: 35)

LSQEQLE X RERSLQ X LRDIQRBLF;

(SEQ ID NO: 36)

LSQEQLEH X ERSLQT X RDIQRBLF;

(SEQ ID NO: 37)

LSQEQLEHR X RSLQTL X DIQRBLF;

(SEQ ID NO: 38)

LSQEQLEHRE X SLQTLR X IQRBLF;

(SEQ ID NO: 39)

LSQEQLEHRER X LQTLRD X QRBLF;

(SEQ ID NO: 40)

LSQEQLEHRERS X QTLRDI X RBLF;

(SEQ ID NO: 41)

LSQEQLEHRERSL X TLRDIQ X BLF;

(SEQ ID NO: 42)

LSQEQLEHRERSLQ X LRDIQR X LF;

(SEQ ID NO: 43)

LSQEQLEHRERSLQT X RDIQRB X F;

or

(SEQ ID NO: 44)

LSQEQLEHRERSLQTL X DIQRBL X;

i, i + 3 single staples:

(SEQ ID NO: 45)

X SQ X QLEHRERSLQTLRDIQRBLF;

(SEQ ID NO: 46)

L X QE X LEHRERSLQTLRDIQRBLF;

(SEQ ID NO: 47)

LS X EQ X EHRERSLQTLRDIQRBLF;

(SEQ ID NO: 48)

LSQE X LE X RERSLQTLRDIQRBLF;

(SEQ ID NO: 49)

LSQEQ X EH X ERSLQTLRDIQRBLF;

(SEQ ID NO: 50)

LSQEQL X HR X RSLQTLRDIQRBLF;

(SEQ ID NO: 51)

LSQEQLE X RE X SLQTLRDIQRBLF;

(SEQ ID NO: 52)

LSQEQLEH X ER X LQTLRDIQRBLF;

(SEQ ID NO: 53)

LSQEQLEHR X RS X QTLRDIQRBLF;

(SEQ ID NO: 54)

LSQEQLEHRE X SL X TLRDIQRBLF;

(SEQ ID NO: 55)

LSQEQLEHRER X LQ X LRDIQRBLF;

(SEQ ID NO: 56)

LSQEQLEHRERS X QT X RDIQRBLF;

(SEQ ID NO: 57)

LSQEQLEHRERSL X TL X DIQRBLF;

(SEQ ID NO: 58)

LSQEQLEHRERSLQ X LR X IQRBLF;

(SEQ ID NO: 59)

LSQEQLEHRERSLQT X RD X QRBLF;

(SEQ ID NO: 60)

LSQEQLEHRERSLQTL X DI X RBLF;

(SEQ ID NO: 61)

LSQEQLEHRERSLQTLR X IQ X BLF;

(SEQ ID NO: 62)

LSQEQLEHRERSLQTLRD X QR X LF;

(SEQ ID NO: 63)

LSQEQLEHRERSLQTLRDI X RB X F;

or

(SEQ ID NO: 64)

LSQEQLEHRERSLQTLRDIQ X BL X ;

a therapeutic agent; and

a pharmaceutically acceptable carrier, and

wherein B is norleucine.

15 . A pharmaceutical composition comprising a BCL9 HD2 stapled peptide, wherein a hydrocarbon staple links the positions designated as X within any one of the following BCL9 HD2 stapled peptides:

Mixed i, i + 4; i, i + 3; and

i, i + 7 double staples:

(SEQ ID NO: 74)

X SQE X LEHRERSLQTL X DIQRBL X ;

(SEQ ID NO: 75)

X SQE X LEHRERSLQT X RDIQRB X F;

(SEQ ID NO: 76)

X SQE X LEHRERSLQ X LRDIQR X LF;

(SEQ ID NO: 77)

X SQE X LEHRERSLQTLRDIQ X BL X ;

(SEQ ID NO: 78)

X SQE X LEHRERSLQTLRDI X RB X F;

(SEQ ID NO: 79)

X SQE X LEHRERSLQTLRD X QR X LF;

(SEQ ID NO: 80)

X SQEQLE X RERSLQTLRDI X RBL X ;

(SEQ ID NO: 81)

X SQEQLE X RERSLQTLRD X QRB X F;

(SEQ ID NO: 82)

X SQEQLE X RERSLQTLR X IQR X LF;

(SEQ ID NO: 83)

X SQEQLE X RERSLQTLRDIQ X BL X ;

(SEQ ID NO: 84)

X SQEQLE X RERSLQTLRDI X RB X F;

(SEQ ID NO: 85)

X SQEQLE X RERSLQTLRD X QR X LF;

(SEQ ID NO: 86)

X SQ X QLEHRERSLQTLRDI X RBL X ;

(SEQ ID NO: 87)

X SQ X QLEHRERSLQTLRD X QRB X F;

(SEQ ID NO: 88)

X SQ X QLEHRERSLQTLR X IQR X LF;

(SEQ ID NO: 89)

X SQ X QLEHRERSLQTL X DIQRBL X ;

(SEQ ID NO: 90)

X SQ X QLEHRERSLQT X RDIQRB X F;

or

(SEQ ID NO: 91)

X SQ X QLEHRERSLQ X LRDIQR X LF;

Sequential i, i + 4 staples:

(SEQ ID NO: 92)

X SQE X LEH X ERSLQTLRDIQRBLF;

(SEQ ID NO: 93)

L X QEQ X EHR X RSLQTLRDIQRBLF;

(SEQ ID NO: 94)

LS X EQL X HRE X SLQTLRDIQRBLF;

(SEQ ID NO: 95)

LSQ X QLE X RER X LQTLRDIQRBLF;

(SEQ ID NO: 96)

LSQE X LEH X ERS X QTLRDIQRBLF;

(SEQ ID NO: 97)

LSQEQ X EHR X RSL X TLRDIQRBLF;

(SEQ ID NO: 98)

LSQEQL X HRE X SLQ X LRDIQRBLF;

(SEQ ID NO: 99)

LSQEQLE X RER X LQT X RDIQRBLF;

(SEQ ID NO: 100)

LSQEQLEH X ERS X QTL X DIQRBLF;

(SEQ ID NO: 101)

LSQEQLEHR X RSL X TLR X IQRBLF;

(SEQ ID NO: 102)

LSQEQLEHRE X SLQ X LRD X QRBLF;

(SEQ ID NO: 103)

LSQEQLEHRER X LQT X RDI X RBLF;

(SEQ ID NO: 104)

LSQEQLEHRERS X QTL X DIQ X BLF;

(SEQ ID NO: 105)

LSQEQLEHRERSL X TLR X IQR X LF;

(SEQ ID NO: 106)

LSQEQLEHRERSLQ X LRD X QRB X F;

or

(SEQ ID NO: 107)

LSQEQLEHRERSLQT X RDI X RBL X ;

Sequential i, i + 3 staples:

(SEQ ID NO: 108)

X SQ X QL X HRERSLQTLRDIQRBLF;

Sequential i, i + 7 staples:

(SEQ ID NO: 109)

X SQEQLE X RERSLQ X LRDIQRBLF;

Mixed sequential staples:

(SEQ ID NO: 110)

X SQ X QLE X RERSLQTLRDIQRBLF;

(SEQ ID NO: 111)

X SQ X QLEHRE X SLQTLRDIQRBLF;

(SEQ ID NO: 112)

X SQE X LE X RERSLQTLRDIQRBLF;

(SEQ ID NO: 113)

X SQE X LEHRER X LQTLRDIQRBLF;

(SEQ ID NO: 114)

X SQEQLE X RE X SLQTLRDIQRBLF;

or

(SEQ ID NO: 115)

X SQEQLE X RER X LQTLRDIQRBLF;

a therapeutic agent; and

a pharmaceutically acceptable carrier, and

wherein B is norleucine.

16 . A pharmaceutical composition comprising the amino acid sequence of:

SAH-BCL9 A :

(SEQ ID NO: 3)

LSQEQLEHRERSLQTLR X IQR X LF,

a therapeutic agent and a pharmaceutically acceptable carrier, wherein X is a staple position.

17 . A pharmaceutical composition comprising the amino acid sequence of:

SAH-BCL9 B : 

(SEQ ID NO: 4)

LSQEQLEHRERSL X TLR X IQRBLF),

a therapeutic agent and a pharmaceutically acceptable carrier, and wherein X is a staple position, and wherein B is norleucine.

Assignments (2)
CONFIRMATORY LICENSE Recorded Jul 26, 2023
From: DANA-FARBER CANCER INST
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 064388/0625 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 19, 2021
From: WALENSKY, LOREN D.; CARRASCO, RUBEN; BIRD, GREGORY H.
To: DANA-FARBER CANCER INSTITUTE, INC.
Reel/Frame 059190/0727 →
Continuity (4)
Continuation 16876779 · May 18, 2020
Division 14111299
Provisional Application 61475932 · Apr 15, 2011
Related Publication 20220204572A1 · Jun 30, 2022
References Cited (77)
US 7084244B2 · Gilon et al. · 2006 [cited by applicant]
US 7192713B1 · Verdine et al. · 2007 [cited by applicant]
US 7723469B2 · Walensky et al. · 2010 [cited by applicant]
US 10703785B2 · Walensky et al. · 2020 [cited by applicant]
US 11220532B2 · Walensky et al. · 2022 [cited by applicant]
US 20020086986A1 · Basler et al. · 2002 [cited by applicant]
US 20050250680A1 · Walensky et al. · 2005 [cited by applicant]
US 20060008848A1 · Verdine et al. · 2006 [cited by applicant]
US 20060014675A1 · Arora et al. · 2006 [cited by applicant]
US 20070197772A1 · Arora et al. · 2007 [cited by applicant]
US 20100234563A1 · Arora et al. · 2010 [cited by applicant]
US 20140113857A1 · Walensky et al. · 2014 [cited by applicant]
CN 1852974 · 2006 [cited by applicant]
CN 1906209 · 2007 [cited by applicant]
EP 1997828 · 2008 [cited by applicant]
WO WO2005005601 · 2005 [cited by applicant]
WO WO2005044839 · 2005 [cited by applicant]
WO WO2008121767 · 2008 [cited by applicant]
WO WO2009108261 · 2009 [cited by applicant]
WO WO2010148335 · 2010 [cited by applicant]
WO WO2011008260 · 2011 [cited by applicant]
National Cancer Institute (https://www.cancer.gov/about-cancer/treatment/drugs/doxorubicinhydrochloride, Aug. 10, 2007). [cited by examiner]
Aans.org, [online], “Brain Tumors,” 2021, retrieved on Apr. 26, 2021, retrieved from URL<https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Brain-Tumors>, 12 pages. [cited by applicant]
Barker et al., “Mining the Wnt pathway for cancer therapeutics,” Nat Rev Drug Discov, 2006, 5:997-1014. [cited by applicant]
Basu et al., “Overexpression of Vascular Endothelial Growth Factor and the Development of Post-Transplantation Cancer,” Cancer Res, 2008, 68(14):5689-98. [cited by applicant]
Bernal et al., “Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide,” J Am Chem Soc, 2007, 129(9):2456-7. [cited by applicant]
Bird et al., “Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic,” PNAS, Aug. 10, 2010, 107(32):14093-14098. [cited by applicant]
Bird et al., “Synthesis and Biophysical Characterization of Stabilized a-Helices of BCL-2 Domains,” Methods Enzymol, 2008, Chapter 22, 446:369-86. [cited by applicant]
Bolstad et al., “A comparison of normalization methods for high density oligonucleotide array data based on variance and bias,” Bioinformatics, 2003, 19(2)185-93. [cited by applicant]
Brembeck et al., “Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions,” Genes Dev, 2004, 18(18): 2225-30. [cited by applicant]
Cancer.gov, [online], “What is Cancer?,” Feb. 9, 2015, retrieved on Apr. 26, 2021, retrieved from URL<https://www.cancer.gov/about-cancer/understanding/what-is-cancer>, 9 pages. [cited by applicant]
Chan et al., “Targeted inactivation of CTNNB1 reveals unexpected effects of beta-catenin mutation,” Proc Natl Acad Sci USA, Jun. 2002, 99(12):8265-70. [cited by applicant]
Chapman et al., “A highly stable short alpha-helix constrained by a main-chain hydrogen-bond surrogate,” J. Am. Chem. Soc., 2004, 126(39):12252-3. [cited by applicant]
Chittenden et al., “A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions,” Embo Journal, 1995, 14(22):5589-5596. [cited by applicant]
Clevers, “Wntβ Catenin Signaling in Development and Disease,” Cell, 2006, 127(3):469-80. [cited by applicant]
Cook, “Anticancer drugs are not enough to conquer cancer,” Shanghai People's Publishing House. Dr. Folkman's War: Angiogenesis and the Struggle to Defeat Cancer, 2001, pp. 159-160, 7 pages (with English Abstract). [cited by applicant]
Dejana, “The Role of Wnt Signaling in Physiological and Pathological Angiogenesis,” Circulation Research, 2010, 107(8):943-952. [cited by applicant]
Deka et al., “Bc19/Bc191 are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas,” Cancer Res, 70(16):6619-28. [cited by applicant]
Ellenberger et al., “The GCN4 basic region leucine zipper binds DNA as a dimer of uninterrupted alpha helices: crystal structure of the protein-DNA complex,” Cell, 1992, 71(7):1223-1237. [cited by applicant]
Extended European Search Report in European Appln. No. 12771731.2, dated Nov. 6, 2014, 3 pages. [cited by applicant]
Extended European Search Report in European Appln. No. 18164082.2, dated May 15, 2018, 6 pages. [cited by applicant]
Extended European Search Report in European Appln. No. 20172306.1, dated Jul. 28, 2020, 2 pages. [cited by applicant]
Gsea-msigdb.org, “UCSan Diego Overview,” 2020, retrieved on Feb. 10, 2021, retreived from URL<https://www.gsea-msigdb.org/gsea/index.jsp>, 1 page. [cited by applicant]
Ilyas et al., “Beta-catenin mutations in cell lines established from human colorectal cancers,” Proc Natl Acad Sci USA, 1997, 94(19):10330-4. [cited by applicant]
Kawamoto et al., “Design of triazole-stapled BCL9 α-helical peptides to target the β-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction,” Journal of Medicinal Chemistry, 2011, 55(3):1137-1146. [cited by applicant]
Kawamoto, “Targeting the BCL9/B9L Binding Interaction with Beta-catenin as a Potential Anticancer Strategy,” Ph.D. Thesis, University of Michigan (2010), 146 pages. [cited by applicant]
Kim et al., “Introduction of All-Hydrocarbon I, i+3 staples into a-helices via Ring-closing Olefin Metathesis,” Organic Letters, 2010, 12(13):3046-3049. [cited by applicant]
Klaus et al., “Wnt signalling and its impact on development and cancer,” Nat Rev Cancer, 2008, 8(5):387-98. [cited by applicant]
Kussie et al., “Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain,” Science, 1996, 274(5289):948-953. [cited by applicant]
Lepourcelet et al., “Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex,” Cancer Cell, 2004, 5(1):91-102. [cited by applicant]
Liu et al., “Engineering a tRNA and aminoacyl-tRNA synthetase for the site-specific incorporation of unnatural amino acids into proteins in vivo,” Proc. Nat. Acad. Sci USA, 1997, 94(19):10092-10097. [cited by applicant]
Logan et al., “The Wnt signaling pathway in development and disease,” Annu Rev Cell Dev Biol, 2004, 20:781-810. [cited by applicant]
Lupas et al., “Predicting coiled coils from protein sequences,” Science, 1991, 252(5009):1162-1164. [cited by applicant]
Mahon et al., “Design, synthesis and protein-targeting properties of thioether-linked hydrogen bond surrogate helices,” Chem. Commun. (Camb)., 2012, 48(10):1416-1418. [cited by applicant]
Mani et al., “BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to cancer cells,” Cancer Res, 2009, 69(19):7577-86. [cited by applicant]
McCarthy et al., “Testing significance relative to a fold-change threshold is a TREAT,” Bioinformatics, 2009, 25(6):765-71. [cited by applicant]
Mollering et al., “Direct inhibition of the NOTCH transcription factor complex,” Nature, 2009, 462(7270):182-8. [cited by applicant]
Naldini et al., “Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector,” PNAS, 1996, 93(21):11382-8. [cited by applicant]
Ncbi.nlm.nih.gov, “Gene Exression Omnibus,” 2020, retrieved on Feb. 10, 2021, retrieved from URL<https://www.ncbi.nlm.nih.gov/geo/>, 1 page. [cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2012/033822, Oct. 15, 2013, 8 pages. [cited by applicant]
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2012/033822, dated Nov. 8, 2012, 11 pages. [cited by applicant]
Pitter et al., “Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains,” Methods Enzymol., 2008, Chapter 23, 446:387-408. [cited by applicant]
Sampietro et al., “Crystal Structure of a 13-Catenin BCL9 Tcf4 Complex,” Mol Cell, 2006, 24(2):293-300. [cited by applicant]
Schafmeister et al., “An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides,” Chem Soc, 2000, 122(24):5891-5892. [cited by applicant]
Shang et al., “Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription,” Cell, 2000, 103(6):843-52. [cited by applicant]
Shuai et al., “Research on BCL9 with Tumor and Tumor Target Treatment,” Life Science Research, 2013, 17(1):86-89. [cited by applicant]
Smyth, “Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments,” Statistical Applications in Genetics and Molecular Biology, 2004, 3(1):Article 3, 28 pages. [cited by applicant]
Subramanian et al., “Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles,” Proc Natl Acad Sci USA, 2005, 102(43):15545-50. [cited by applicant]
Sukhdeo et al., “Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma,” Proc Natl Acad Sci USA, 2007, 104(18):7516-21. [cited by applicant]
Sustmann et al., “Cell-type-specific function of BCL9 involves a transcriptional activation domain that synergizes with beta-catenin,” Mol Cell Biol, 2008, 28(10):3526-37. [cited by applicant]
Sythetic Peptides A User's Guide, 2nd Ed., 2002, Chapter 3, 139 pages. [cited by applicant]
Takada et al., “Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling,” Science Translational Medicine, 2012, 4(148):148ra117, 26 pages. [cited by applicant]
Tassone et al., “A clinically relevant SCID-hu in vivo model of human multiple myeloma,” Blood, 2005, 106(2):713-6. [cited by applicant]
Van der Flier et al., “The Intestinal Wnt TCF Signature,” Gastroenterology, 2007, 132(2):628-32. [cited by applicant]
Vermeulen et al., “Wnt activity defines colon cancer stem cells and is regulated by the microenvironment,” Nat Cell Biol., 2010, 12(5):468-76. [cited by applicant]
Walensky et al., “Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix,” Science, 2004, 305(5689):1466-70. [cited by applicant]
Walensky et al., “Hydrocarbon-stapled peptides: principles, practice, and progress,” J Med Chem., 2014, 7(15):6275-88. [cited by applicant]