- Structure-activity relationships of N-terminal variants of peptidomimetic tissue transglutaminase inhibitors
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Tissue transglutaminase (TG2) is a multifunctional protein that catalyses protein crosslinking in the extracellular matrix, and functions as an intracellular G-protein. While both activities have been associated with human diseases, its role as a G-protein has been linked to cancer stem cell survival and maintenance of a metastatic phenotype. Recently we have shown that targeted covalent inhibitors (TCIs) can react selectively with the enzyme active site of TG2, to allosterically abolish its ability to bind GTP. In the present work, we focused on the variation of the N-terminal group of these peptidomimetic inhibitors, in order to enhance efficiency, while reducing log P and the number of rotatable bonds. This approach led to the synthesis and evaluation of 41 novel inhibitors, some of which had greatly improved efficiency and affinity for TG2 (e.g. TCI 72: KI = 1.0 μM, kinact/KI = 4.4 × 105 M?1 min?1). Molecular modelling provided a hypothetical binding mode for these TCIs. The most efficient inhibitors were evaluated further and shown to have excellent isozyme selectivity, to block GTP binding, and to have improved pharmacokinetic properties, as expected. Their biological activity was also confirmed, in a cellular invasion assay, although with less potency than expected.
- Adhikary, Gautam,Cundy, Nicholas J.,Eckert, Richard L.,Eisinga, Sarah,Firoozi, Neda,Gates, Eric W. J.,Keillor, Jeffrey W.,Leccese, Jessica,McNeil, Nicole M. R.,Tyndall, Joel D. A.
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- Novel monoacylglycerol lipase inhibitor as well as preparation method and application thereof
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The invention discloses a novel monoacylglycerol lipase inhibitor as well as a preparation method and application thereof. Specifically, the invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated derivative thereof. Experimental results show that the compound provided by the invention can effectively inhibit MAGL activity, can beused for preparing an MAGL inhibitor and preparing medicines for preventing and/or treating diseases (including endometrial cancer, colorectal cancer, liver cancer, breast cancer, ovarian cancer, neurodegenerative diseases and the like) related to abnormal MAGL activity, and has a wide application prospect.
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Paragraph 0184-0187
(2021/02/10)
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- Structure-Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
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Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been associated with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, we present a series of targeted covalent inhibitors (TCIs) based on our previously reported Cbz-Lys scaffold. From this structure-activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (kinact/KI > 105 M-1 min-1). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC50 of 3.9 μM, representing a significant improvement over our previously reported "hit" NC9.
- Akbar, Abdullah,McNeil, Nicole M. R.,Albert, Marie R.,Ta, Viviane,Adhikary, Gautam,Bourgeois, Karine,Eckert, Richard L.,Keillor, Jeffrey W.
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p. 7910 - 7927
(2017/10/06)
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- SUBSTITUTED PIPERAZINES, (1,4) DIASZEPINES, AND 2,5-DIAZABICYCLO (2.2.1) HEPTANES AS HISTAMINE H1 AND/OR H3 ANTAGONISTS OR HISTAMINE H3 REVERSE ANTAGONISTS
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The present invention relates to novel piperazine and azepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurodegenerative disorders including Alzheimer's disease.
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