Agents modulating beta-catenin functions and methods thereof
Inventors
HILINSKI, Gerard • Shim, So Youn • Patton, Matthew Reiser • MCGEE, John Hanney • Ortet, Paula • Verdine, Gregory L.
Assignees
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Publication Number
US-11198713-B2
Publication Date
2021-12-14
Expiration Date
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.
Core Innovation
The invention relates to stapled peptides in which side chains are linked together to form a staple. The peptide comprises amino acid residues at positions p1, p2, p11, p12, and p13, each independently 0 or 1, and X1 through X13 are independently amino acid residues, with at least two of the residues comprising side chains linked together to form a staple. The peptide comprises a structure selected from stapled peptide configurations shown in the patent.
The described embodiments include peptides comprising two or more staples, as well as connectivity constraints in which at least two staples are bonded to the same peptide backbone atom or no two staples are bonded to the same peptide backbone atom. The representations include labeled positions such as X6 and stereochemical designations including (R) and (S), together with variable staple/linker geometries within a common peptide backbone framework.
Additional structurally specific embodiments define a peptide, or a pharmaceutically acceptable salt thereof, having constrained R-group, linker, ring, and bivalent-group definitions, including Ls linker segments bonded to C1 and C2. These peptides comprise two or more staples and a structure selected from stapled configurations shown in the patent, and some embodiments are extended to pharmaceutical compositions with a pharmaceutically acceptable carrier.
Claims Coverage
The independent claims cover stapled peptides defined by amino-acid residue positions and side-chain-linked staple structures, with coverage for both one/no-more-than-one staple and two-or-more-staple regimes. Additional independent scope includes a highly specified peptide scaffold with constrained variable groups and linker definitions, and some claims extend to pharmaceutical compositions. The inventive features are the staple-forming peptide structure, staple count and backbone-attachment constraints, and the parameterized scaffold.
Side-chain linked staple peptide structure
A peptide in which p1, p2, p11, p12, and p13 are independently 0 or 1, each X1 through X13 is independently an amino acid residue, and at least two of the residues comprise side chains linked together to form a staple, with the peptide comprising a structure selected from shown staple configurations.
Two or more side-chain linked staples
A peptide in which p1, p2, p11, p12, and p13 are independently 0 or 1, each X1 through X13 is independently an amino acid residue, at least two of the residues comprise side chains linked together to form a staple, and the peptide comprises two or more staples, with the peptide comprising a structure selected from shown staple configurations.
Staple bonding constraint relative to a peptide backbone atom
A peptide comprising two or more staples, where at least two staples are bonded to the same peptide backbone atom, or alternatively where no two staples are bonded to the same peptide backbone atom.
Highly specified stapled peptide scaffold with constrained linker and substituent rules
A peptide, or a salt thereof, having a structure with defined R-group options, ranges for a and for b, c, s, and d, carbon atoms C1 and C2, and linker units Ls bonded to C1 and C2, where the peptide comprises two or more staples and comprises a structure selected from shown staple configurations.
Overall, the claims center on stapled peptides whose linked side chains form staple structures selected from the patent’s representations. The scope distinguishes staple count regimes, includes backbone-attachment constraints for multiple staples, and separately claims a highly constrained stapled-peptide scaffold with defined variable groups and linker rules, including peptide salts and pharmaceutical compositions.
Stated Advantages
Improved yields associated with preferred staple lengths, including 11+ atoms and 10–14 atoms for specific types.
Different staple types affect olefin metathesis product formation and the rate of staple formation.
Functional and binding characterization is provided comparing amino staples and carbamate staples, including that amino staples can have lower binding affinity than carbamate staples.
Documented Applications
Therapeutic use for β-catenin/Wnt-associated diseases, including cancers.
Functional evaluation related to a beta-catenin TCF/LEF reporter, including TCF/LEF reporter inhibition at 10 μM.
Binding analysis using Surface Plasmon Resonance (SPR) and Biacore to obtain Kd values for staple types.
Olefin-metathesis stapling outcomes characterized for stapled peptide sequences, including reaction completeness, byproduct formation, and formation of double isomers after single versus double treatment.
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