TG2 inhibitor piperazine compounds and uses thereof
Inventors
Keillor, Jeffrey W. • AKBAR, Abdullah • Eckert, Richard L. • Fisher, Matthew • JOHNSON, Gail V. W.
Assignees
University of Ottawa • University of Maryland Baltimore • University of Rochester
Publication Number
US-10894777-B2
Publication Date
2021-01-19
Expiration Date
2037-04-13
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Abstract
There are provided Tissue Transglutaminase (TG2) inhibitor compounds, and compositions and methods of use thereof for the prevention or treatment of a cancer. Compounds of Formula I, and pharmaceutically acceptable salts thereof, are provided:
Core Innovation
The invention provides Tissue Transglutaminase 2 (TG2) inhibitor compounds of Formula I and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising these compounds, and methods of their use for the prevention or treatment of cancer. These TG2 inhibitor compounds act by inhibiting one or more activities of TG2, including GTPase activity, GTP binding activity, and transamidation activity. Some compounds act as conformational modulators holding TG2 in an open conformation that does not bind GTP. The invention includes irreversible inhibitors that covalently bind to the active site and lock TG2 in an open conformation, thereby abrogating transamidation and GTP binding activities.
The problem being solved addresses the deficiencies in prior art relating to cancer treatment, specifically the need for novel anti-cancer therapies that target cancer stem cells (CSCs) and cells undergoing epithelial to mesenchymal transition (EMT) which are refractory to current inhibitors. TG2 is implicated in tumor proliferation, survival, EMT maintenance, drug resistance, and cancer recurrence. Despite existing TG2 inhibitors, prior art compounds may have high P-glycoprotein efflux rates making them unsuitable for crossing the blood-brain barrier and are not potent enough in vivo. Thus, more potent, selective TG2 inhibitors capable of preventing or treating cancer, including drug-resistant and recurrent cancers, are needed.
The invention further provides detailed chemical structures of the inhibitor compounds (Formula I and II), methods for inhibiting TG2 activity in vitro and in subjects by administering effective amounts of these compounds, and pharmaceutical compositions comprising these compounds and carriers. Therapeutic uses include treatment of various cancers such as blood-cell derived cancers, solid tumors including glioblastoma multiforme (GBM) and epidermal squamous cell carcinoma (SCC). The compounds may also sensitize resistant cancers to chemotherapeutic agents, prevent cancer recurrence and metastasis, including inhibition of EMT and CSC survival, migration and invasion.
Claims Coverage
The patent claims cover one independent chemical composition claim, pharmaceutical composition claims, and method claims for inhibiting TG2 activity in cells and subjects using the compounds.
Compound of Formula I
A compound defined by Formula I, including specific substituents R1, R2, and n, with examples such as VA4, VA5, and AA9, or their pharmaceutically acceptable salts.
Pharmaceutical composition
Compositions comprising a compound of Formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Method of inhibiting TG2 activity in a cell
A method comprising contacting TG2 in a cell with a compound of Formula I or its pharmaceutically acceptable salt to inhibit TG2 activities such as guanosine triphosphatase activity, GTP binding activity, and transamidation activity, and/or holding TG2 in an open conformation.
Method of inhibiting TG2 activity in a subject
A method comprising administering to a subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt to inhibit one or more TG2 activities including guanosine triphosphatase activity, GTP binding activity, and transamidation activity.
The claims define novel piperazine compounds of Formula I as potent, irreversible TG2 inhibitors that inhibit multiple TG2 activities and their use in pharmaceutical compositions and methods to treat cancer by inhibiting TG2 in cells and subjects.
Stated Advantages
The compounds are potent irreversible TG2 inhibitors that inhibit multiple activities of TG2 including GTPase activity, GTP binding, and transamidation.
They hold TG2 in an open conformation that abolishes GTP binding, contrasting with prior inhibitors that do not inhibit GTP binding.
The inhibitors demonstrate efficacy in reducing proliferation, migration, invasion, and survival of cancer stem cells and drug-resistant cancer cells, thus addressing key problems in current cancer therapy.
The inhibitors exhibit minimal toxicity toward non-cancerous cells such as neurons.
Documented Applications
Prevention and treatment of cancers including blood-cell derived cancers such as lymphoma, leukemia, and myeloma.
Treatment of solid organ tumors including tumors of colon, breast, lung, prostate, brain, pancreas, ovary, and skin.
Specifically treating gliomas such as malignant gliomas and glioblastoma multiforme (GBM).
Treating epidermal squamous cell carcinoma (SCC).
Treatment of drug- or chemo-resistant cancers, sensitization or re-sensitization of cancers to chemotherapy.
Prevention or inhibition of cancer recurrence, especially after surgical excision.
Inhibition of metastasis via preventing or inhibiting the epithelial to mesenchymal transition (EMT).
Inhibition of cancer stem cell (CSC) survival, proliferation, and spheroid formation.
Inhibition of tumor progression, growth, migration, and invasion including malignant glial cell invasion.
Enhancement of efficacy of cancer therapies including surgical resection, chemotherapy, radiation therapy, immunotherapy, and gene therapy.
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