Agents modulating beta-catenin functions and methods thereof

Inventors

HILINSKI, Gerard • Shim, So Youn • Patton, Matthew Reiser • MCGEE, John Hanney • Ortet, Paula Cristina • Verdine, Gregory L

Assignees

Parabilis Medicines Inc

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 staple-containing peptides in which amino acid residue positions X1 through X13 are defined, and at least two of the X residues comprise side chains linked together to form a staple. The peptide comprises a structure selected from disclosed staple-containing structures, including embodiments with a segment labeled X6 and stereochemical labeling at R and S positions.

In some embodiments, the peptide comprises two or more staples, and the claims further constrain how staples bond relative to the peptide backbone atoms, including embodiments where at least two staples are bonded to the same peptide backbone atom or where no two staples are bonded to the same peptide backbone atom. The description also includes specific peptide structures with variable residue and linker definitions, including R, R1-R4, Rb, Ls, and Ls1-Ls3, together with constrained attachment relationships.

The patent content also describes stapled peptides with explicit problem framing around improved solubility and improved pharmacokinetics/half-life after dosing. Additional disclosed embodiments relate to functional modulation of beta-catenin interactions, including selective disruption or modulation using Axin over BCL9, together with examples and datasets for solubility, pharmacokinetic analysis, competition fluorescence polarization, and SPR Kd referenced measurements.

Claims Coverage

The consolidated claim coverage includes three independent peptide claim themes, with multiple staple-containing structural scopes and corresponding pharmaceutical composition coverage. Across the claims, the inventive features center on staple-forming side-chain linkages among amino acid residue positions X1-X13, selection from disclosed staple-containing structural variants, constraints on the number and placement of staples, and, for one claim set, a highly variable substituted peptide framework with linker and group definitions.

Overall, the claims cover staple-containing peptides defined by linked side chains at residue positions X1-X13, with claim scope further distinguished by the presence of two or more staples, by staple-to-backbone atom relationships, and by a structurally specific variable peptide framework. The claim set also extends to pharmaceutical compositions containing the peptide, or its pharmaceutically acceptable salt, with a pharmaceutically acceptable carrier.

Stated Advantages

Documented Applications