Abstract: Among other things, the present disclosure provides technologies for modulating functions of beta-catenin. In some embodiments, the present disclosure provides stapled peptides that interact with beta-catenin. In some embodiments, provided stapled peptides interact with beta-catenin at an Axin-binding site of beta-catenin. In some embodiments, the present disclosure provides compounds, compositions and methods for preventing and/or treating conditions, disorders and diseases that are associated with beta-catenin.

Abstract: The present invention provides stapled polypeptides of the Formulae (I) and (VI): and salts thereof; wherein the groups ; R1a, R1b, R1c, R2a, R3a, R2b, R3b, R4a, R4b, RA, RZ, L1a, L1b, L2, L3, XAA, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.

Abstract: Among other things, the present disclosure provides technologies for modulating functions of beta-catenin. In some embodiments, the present disclosure provides stapled peptides that interact with beta-catenin. In some embodiments, provided stapled peptides interact with beta-catenin at an Axin-binding site of beta-catenin. In some embodiments, the present disclosure provides compounds, compositions and methods for preventing and/or treating conditions, disorders and diseases that are associated with beta-catenin.

Abstract: The present invention provides stapled polypeptides of the Formulae (I) and (VI): and salts thereof; wherein the groups ; R1a, R1b, R1c, R2a, R3a, R2b, R3b, R4a, R4b, RA, RZ, L1a, L1b, L2, L3, XAA, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.

Abstract: Described herein is an operationally simple, one-pot solid-supported preparation of saturated stapled peptides. Following completion of ruthenium-catalysed metathesis, solid-phase transfer hydrogenation was achieved using triethylhydrosilane at elevated temperatures. The utility of the method has been demonstrated on 14- and 16-mer peptides to yield the corresponding cyclic a-helix stabilised stapled peptides.

Abstract: Among other things, the present disclosure provides technologies for modulating functions of beta-catenin. In some embodiments, the present disclosure provides stapled peptides that interact with beta-catenin. In some embodiments, provided stapled peptides interact with beta-catenin at an Axin-binding site of beta-catenin. In some embodiments, the present disclosure provides compounds, compositions and methods for preventing and/or treating conditions, disorders and diseases that are associated with beta-catenin.

Abstract: Described herein is an operationally simple, one-pot solid-supported preparation of saturated stapled peptides. Following completion of ruthenium-catalysed metathesis, solid-phase transfer hydrogenation was achieved using triethylhydrosilane at elevated temperatures. The utility of the method has been demonstrated on 14- and 16-mer peptides to yield the corresponding cyclic a-helix stabilised stapled peptides.

Abstract: The present invention provides stapled polypeptides of the Formulae (I) and (VI): and salts thereof; wherein the groups ; R1a, R1b, R1c, R2a, R3a, R2b, R3b, R4a, R4b, RA, RZ, L1a, L1b, L2, L3, XAA, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.

Abstract: Among other things, the present disclosure provides technologies for modulating functions of beta-catenin. In some embodiments, the present disclosure provides stapled peptides that interact with beta-catenin. In some embodiments, provided stapled peptides interact with beta-catenin at an Axin-binding site of beta-catenin. In some embodiments, the present disclosure provides compounds, compositions and methods for preventing and/or treating conditions, disorders and diseases that are associated with beta-catenin.

Abstract: The present invention provides stapled polypeptides of the Formulae (I) and (VI): and salts thereof; wherein the groups ; R1a, R1b, R1c, R2a, R3a, R2b, R3b, R4a, R4b, RA, RZ, L1a, L1b, L2, L3, XAA, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.

Abstract: Provided herein are stabilized ?-CT polypeptides comprising an alpha-helical segment, and wherein the polypeptide is of Formula (I-1) or Formula (I-2): Rf—[XAA]s—XA1—XA2—XA3—XA4—XA5—XA6—XA7—XA8—XA9—XA10—XA11—XA12—XA13—XA14—[XAA]t—Re (I-1) Rf—[XAA]s—XC1—XC2—XC3—XC4—XC5—XC6—XC7—XC8—XC9—XC10—XC11—XC12—XC13—XC14—XC15—XC16—XC17—XC18—XC19—XC20—[XAA]t—Re (I-2) wherein the ?-CT polypeptide binds to the insulin receptor, and wherein the ?-CT polypeptide includes at least one staple (i.e. two cross-linked amino acids) and/or at least one stitch (i.e. three cross-linked amino acids). Further provided are insulin analogs including the stapled or stitched ?-CT polypeptides, pharmaceutical compositions thereof, methods of use, e.g., methods of treating a diabetic condition or complications thereof.

Abstract: The present invention provides stapled polypeptides of the Formulae (I) and (VI): (I) (VI) and salts thereof; wherein the groups ; R1a, R1b, R1c, R2a, R3a, R2b, R3b, R4a, R4b, RA, RZ, L1a, L1b, L2, L3, XAA, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.

Abstract: Provided herein are stabilized ?-CT polypeptides comprising an alpha-helical segment, and wherein the polypeptide is of Formula (I-1) or Formula (I-2): Rf—[XAA]s—XA1—XA2—XA3—XA4—XA5—XA6—XA7—XA8—XA9—XA10—XA11—XA12—XA13—XA14—[XAA]t—Re (I-1) Rf—[XAA]s—XC1—XC2—XC3—XC4—XC5—XC6—XC7—XC8—XC9—XC10—XC11—XC12—XC13—XC14—XC15—XC16—XC17—XC18—XC19—XC20—[XAA]t—Re (I-2) wherein the ?-CT polypeptide binds to the insulin receptor, and wherein the ?-CT polypeptide includes at least one staple (i.e. two cross-linked amino acids) and/or at least one stitch (i.e. three cross-linked amino acids). Further provided are insulin analogues including the stapled or stitched ?-CT polypeptides, pharmaceutical compositions thereof, methods of use, e.g., methods of treating a diabetic condition or complications thereof.

Abstract: The present invention provides stapled polypeptides of the Formulae (I) and (VI): (I) (VI) and salts thereof; wherein the groups =====; R1a, R1b, R1c, R2a, R3a, R2b, R3b, R4a, R4b, RA, RZ, L1a, L1b, L2, L3, XAA, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.