Methods and composition of 4-substituted benzoylpiperazine-1-substituted carbonyls as beta-catenin/B-cell lymphoma 9 inhibitors
Inventors
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Assignees
Universisity Of Utah Research Foundation
Member
University of UtahThe University of Utah (UU) is a leading research institution recognized for its research activity and commitment to innovation and discovery. As an R1 Institution, it is dedicated to advancing knowledge and solving critical problems that challenge our national security interests and impact the global community.
We foster interdisciplinary collaboration and provide resources to drive transformative research focused on enhancing medical care superiority for the U.S. Department of Defense (DoD) through advanced medical and engineering research sponsored by our Applied Medical & Engineering Laboratory (AM&E Lab).
As a leading public university, UU also provides healthcare services to seven states in the Intermountain West, with the largest catchment of remote and austere frontier territory for any academic center. Leveraging its geographic advantage, technological and commercialization strengths, expertise in medical services, and leading-edge, core engineering competencies, UU is uniquely positioned to address the nation's critical national security interests.
The University of Utah (UU) is a leading research institution recognized for its research activity and commitment to innovation and discovery. As an R1 Institution, it is dedicated to advancing knowledge and solving critical problems that challenge our national security interests and impact the global community. We foster interdisciplinary collaboration and provide resources to drive transformative research focused on enhancing medical care superiority for the U.S. Department of Defense (DoD) through advanced medical and engineering research sponsored by our Applied Medical & Engineering Laboratory (AM&E Lab). As a leading public university, UU also provides healthcare services to seven states in the Intermountain West, with the largest catchment of remote and austere frontier territory for any academic center. Leveraging its geographic advantage, technological and commercialization strengths, expertise in medical services, and leading-edge, core engineering competencies, UU is uniquely positioned to address the nation's critical national security interests.
Publication Number
US-11542254-B2
Publication Date
2023-01-03
Expiration Date
2037-03-24
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 and related derivatives that act as inhibitors of β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interactions. The invention encompasses the chemical structures of these compounds, methods for synthesizing them, pharmaceutical compositions containing them, and their use for treating disorders such as various tumors and cancers that are associated with β-catenin/BCL9 pathway dysfunction or Wnt pathway dysregulation.
The problem addressed by this invention is the scarcity of potent, efficacious, and selective inhibitors of β-catenin/BCL9 protein-protein interactions that are also effective in treating cancers and other diseases characterized by uncontrolled cellular proliferation, including fibrotic diseases. Previous efforts have identified only a limited number of drug-like compounds capable of targeting this pathway with appropriate selectivity and activity, and the inhibition of β-catenin/BCL9 PPIs represents a promising target for the treatment of Wnt-driven malignancies without disrupting normal tissue homeostasis.
The invention discloses compounds with specific substituents and a defined core structure that selectively inhibit β-catenin/BCL9 PPI over β-catenin/cadherin PPI, downregulate Wnt signaling, and inhibit the transcription of β-catenin target genes. These compounds are further shown to inhibit cell viability, migration, angiogenesis, tumor metastasis, and tumor progression, thereby addressing unmet therapeutic needs in the management of diseases driven by Wnt pathway dysregulation.
Claims Coverage
There are two independent claims that establish the core inventive features of this patent: the core compound structure with defined substituents and the pharmaceutical composition utilizing the compound.
Compound having a defined 4-substituted benzoylpiperazine-1-substituted carbonyl structure
A compound represented by a chemical formula in which: - A is —N— or —CR8— where R8 is hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl. - L1 is optionally present (O, S, or NH). - L2 is optionally present (O, S, NR9, or —(CR10aR10b)n— with n=1,2,3; R9 and R10 variants permitted as specified). - R1a and R1b, R2a, R2b, R2c, R3, R4, R5, R6, R7, Cy1, Cy2, Cy3, Ar1, and all related substituents are defined explicitly in the claim (with permissible substitutions and alternatives detailed for each position as in the claim text and summary). - The claim covers each permissible combination explicitly recited in the specification by its substituent definitions. - This compound includes all pharmaceutically acceptable salts thereof.
Pharmaceutical composition containing the inventive compound
A pharmaceutical composition comprising a therapeutically effective amount of the compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The claims cover the compound's highly specific chemical structure and its use in pharmaceutical compositions, defining the permissible substituents and salt forms described in the patent.
Stated Advantages
The compound is a potent, efficacious, and selective inhibitor of β-catenin/BCL9 protein-protein interactions, effective for treating cancers and other diseases associated with uncontrolled cellular proliferation.
The compound exhibits high selectivity for β-catenin/BCL9 over β-catenin/cadherin protein-protein interactions.
The compound can downregulate Wnt pathway signaling and inhibit the transcription of β-catenin target genes, thus addressing disease drivers in Wnt pathway dysregulation.
Cell-based studies demonstrate that the compound suppresses canonical Wnt signaling and inhibits growth of cancer cells with hyperactivated Wnt signaling.
Documented Applications
Treatment of disorders associated with β-catenin/BCL9 protein-protein interaction dysfunction, including various tumors and cancers.
Methods for inhibiting protein-protein interactions of β-catenin and BCL9 in mammals and in cells.
Treatment and prevention of disorders of uncontrolled cellular proliferation, such as cancers and fibrotic diseases, including specific cancers like breast, prostate, colon, hematological cancers, and brain cancers.
Use in pharmaceutical compositions for administration to subjects having a disorder of uncontrolled cellular proliferation.
Development and standardization of in vitro and in vivo test systems for evaluation of inhibitors of β-catenin/BCL9 protein-protein interactions in laboratory animals.
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