Peptoid-peptide macrocycles, pharmaceutical compositions and methods of using the same
Inventors
Kirshenbaum, Kent • LOGAN, Susan • Craven, Timothy • KASPER, Amanda • BONNEAU, Richard A. • Schneider, Jeffrey A
Assignees
Publication Number
US-12281180-B2
Publication Date
2025-04-22
Expiration Date
2039-07-12
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Provided are peptoid-peptide macrocycles. The peptoid-peptide macrocycles may have inhibitory activity towards the Wnt signaling pathway. The Wnt signaling pathway is associated with cancer and other diseases and conditions. Such diseases include, for example, pulmonary fibrosis. Also described are methods of making the peptoid-peptide macrocycles, compositions containing the peptoid-peptide macrocycles, and methods of using the peptoid-peptide macrocycles.
Core Innovation
The invention provides peptoid-peptide macrocycles that can inhibit the Wnt signaling pathway, which is implicated in cancer and other diseases such as pulmonary fibrosis. These macrocycles are synthesized as hybrid molecules comprising peptoid monomers and amino acid residues, with structural features intentionally designed to address longstanding challenges in targeting protein-protein interactions (PPIs), specifically those involving β-catenin and the T-Cell Factor (TCF) family of transcription factors. The disclosed compounds include variants where at least one peptoid monomer is replaced by a D- or L-amino acid, expanding the functional diversity of the macrocycles.
The problem addressed by this invention is the current lack of effective therapeutic agents capable of modulating broad and flat protein-protein interaction surfaces, such as those presented by β-catenin—TCF complexes in the Wnt signaling pathway. Existing small molecules often struggle to bind these extended surfaces with sufficient affinity, while peptides are typically unstable and susceptible to degradation. Macrocyclic peptoid-based oligomers, however, can be designed to enforce conformational ordering and present chemically diverse, cell-permeable structures with enhanced pharmacological properties for modulating challenging PPIs.
The disclosure details the design, synthesis, and application of these macrocycles, including computationally guided selection of side chains to optimize binding to β-catenin, resulting in potent inhibition of Wnt signaling both in vitro and in vivo. The macrocycles show efficacy as antagonists of the β-catenin:TCF interaction, inhibit proliferation of prostate cancer cells and other cell lines, and suppress Wnt-induced transcriptional programs. Methods of making the macrocycles, pharmaceutical compositions containing them, and therapeutic methods for treating diseases associated with aberrant Wnt signaling are also described.
Claims Coverage
The patent claims focus on three main inventive features covering peptoid-peptide macrocycles, specific structural embodiments, and related pharmaceutical compositions.
Peptoid-peptide macrocycle with defined core structure
A peptoid-peptide macrocycle having a structure defined by a macrocyclic scaffold that includes both peptoid and peptide (amino acid) residues, where the peptoid is an N-substituted amino acid and the peptide component includes an amino acid residue, and n is an integer (e.g., 1, 2, or 3) dictating the number of repeat units in the macrocycle.
Specified peptoid-peptide macrocycle sequences
Peptoid-peptide macrocycles described by specific sequences and monomer units, with examples provided for defined chemical structures and choices of R substituents in the peptoid and peptide side chains (including methyl substitution and detailed sequence formulas as explicitly recited in the claims).
Pharmaceutical composition containing peptoid-peptide macrocycle
A composition comprising the defined peptoid-peptide macrocycle with a pharmaceutically acceptable carrier, wherein the carrier can be selected from parenteral, oral, or topical carriers suitable for therapeutic administration.
The inventive features cover peptoid-peptide macrocycles with specifically defined structures, explicit sequences, and pharmaceutical compositions containing these macrocycles with versatile administration routes.
Stated Advantages
The macrocyclic structure imposes conformational ordering, enhancing binding energies and specificity for protein surfaces involved in PPIs.
Peptoid-based macrocycles exhibit greater stability against proteolytic degradation compared to peptides.
The chemical diversity and tunable properties of peptoid side chains allow for improved pharmacological characteristics, including cell permeability.
Macrocycles can effectively inhibit targets that are currently considered 'undruggable' by small molecules or unconstrained peptides, such as the β-catenin:TCF interaction.
The disclosed macrocycles show potent inhibitory activity against the Wnt signaling pathway and anticancer activity in in vitro and in vivo models.
Documented Applications
Treatment and prevention of cancers causally related to aberrant Wnt signaling, including prostate, colon, rectal, breast, skin (including melanoma), liver, head and neck, lung, gastric, mesothelioma, Barrett's esophagus, synovial sarcoma, cervical, endometrial ovarian, Wilm's tumor, bladder cancer, and leukemia.
Treatment of pulmonary fibrosis through inhibition of the Wnt/β-catenin pathway.
Restoration of normal cell phenotype and reduction of hyperproliferation in diseases involving dysregulated Wnt signaling.
Use in pharmaceutical compositions administered via oral, parenteral, or topical routes, in both monotherapy and combination therapy regimens with other agents targeting cancer or fibrotic disease.
Amelioration or management of psoriasis linked to elevated Wnt/β-catenin signaling.
Interested in licensing this patent?