Methods and compositions of 4-substituted benzoylpiperazine-1-substituted carbonyls as β-catenin/B-cell lymphoma 9 inhibitors
Inventors
Assignees
University of Utah • University of Utah Research Foundation Inc
Publication Number
US-12286422-B2
Publication Date
2025-04-29
Expiration Date
2037-03-24
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
In one aspect, the invention relates to 4-substituted benzoylpiperazine-1-substituted carbonyls having a structure represented by a formula: derivatives thereof, and related compounds; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders, e.g., various tumors and cancers, associated with β-catenin/BCL9 protein-protein interaction dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to 4-substituted benzoylpiperazine-1-substituted carbonyl compounds, as well as their derivatives and related compounds, which are designed as inhibitors of β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interactions. These compounds are described by specific structural formulas and have been developed along with synthetic methods for making them, pharmaceutical compositions containing the compounds, and methods of treating disorders associated with dysfunction in β-catenin/BCL9 interactions, particularly various tumors and cancers.
The β-catenin/BCL9 interaction is a critical component of the canonical Wnt signaling pathway, which regulates embryonic development, stem cell maintenance, and tissue homeostasis. Dysregulation or hyperactivation of this pathway, especially via dysfunctional β-catenin/BCL9 protein-protein interactions, drives many cancers, tumor progression, metastasis, and fibrotic diseases. Prior attempts to disrupt the β-catenin/BCL9 interaction with small molecules or peptides have had limited success in producing selective, potent, and efficacious inhibitors with drug-like properties applicable to these diseases.
The core innovation thus centers on providing novel compounds with defined chemical structures that selectively inhibit β-catenin/BCL9 protein-protein interactions. These inhibitors can be formulated into pharmaceutical compositions and used to treat disorders of uncontrolled cellular proliferation associated with β-catenin/BCL9 dysfunction or Wnt pathway dysregulation. Methods are presented for synthesizing the compounds, formulating them for pharmaceutical use, and administering them for therapeutic benefit in mammals, including humans.
Claims Coverage
There is one independent claim in the patent, which covers the main inventive feature relating to the treatment of disorders involving β-catenin/BCL9 dysfunction using specific compounds.
Method for treating disorders of uncontrolled cellular proliferation associated with β-catenin/BCL9 dysfunction
A method comprising administering to a mammal an effective amount of at least one compound having a structure represented by a specified formula (as detailed in the claim), or a pharmaceutically acceptable salt thereof, for the treatment of a disorder of uncontrolled cellular proliferation associated with β-catenin/BCL9 dysfunction. - The mammal may include a human identified to have a 1q21 chromosomal abnormality. - The method includes steps for identifying a human in need of treatment by obtaining a sample and determining the presence of a 1q21 chromosomal abnormality. - The cancer being treated can be specifically breast cancer or colorectal cancer (including colorectal cancer).
The claimed invention covers the therapeutic use of a class of specifically structured compounds to treat diseases linked to β-catenin/BCL9 dysfunction, encompassing methods for patient identification, and targeting specific cancers.
Stated Advantages
Provides potent, efficacious, and selective inhibitors of β-catenin/BCL9 interactions, which have been scarce in the treatment of cancers and other diseases associated with uncontrolled cellular proliferation.
Selective disruption of β-catenin/BCL9 interactions does not affect normal tissue homeostasis, focusing therapeutic action on disease tissues.
The invention's compounds and compositions can inhibit Wnt signaling, suppress transcription of β-catenin target genes, and inhibit cancer cell migration, viability, angiogenesis, metastasis, and tumor progression.
Compounds exhibit high selectivity for β-catenin/BCL9 inhibition over β-catenin/cadherin interactions.
The ability to inhibit growth of Wnt-activated cancer cells, including colorectal cancer cell lines, with defined IC50 values.
Documented Applications
Treatment of disorders of uncontrolled cellular proliferation, including cancers, associated with β-catenin/BCL9 protein-protein interaction dysfunction or Wnt pathway dysregulation.
Treatment of various cancers such as breast cancer and colorectal cancer.
Treatment and prevention of fibrotic diseases, including pulmonary fibrosis, liver fibrosis, and polycystic kidney disease.
Use in patients identified as having a 1q21 chromosomal abnormality.
Selective inhibition of β-catenin/BCL9 interactions in cells or mammals, including humans.
Use as pharmacological tools in the development and standardization of in vitro and in vivo test systems for evaluation of inhibitors of β-catenin/BCL9 interactions.
Interested in licensing this patent?