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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-14 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01070 Abdullah Akbar 1 , Nicole M. R. McNeil 1 , Marie R. Albert 1 , Viviane Ta 1 , Gautam Adhikary 2 , Karine Bourgeois 1 , Richard L. Eckert 2 , Jeffrey W. Keillor 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-14 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01070 Abdullah Akbar 1 , Nicole M. R. McNeil 1 , Marie R. Albert 1 , Viviane Ta 1 , Gautam Adhikary 2 , Karine Bourgeois 1 , Richard L. Eckert 2 , Jeffrey W. Keillor 1
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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.
中文翻译：
消除人类组织转谷氨酰胺酶的转酰胺基作用和GTP结合活性的有效，靶向共价抑制剂的构效关系
人体组织转谷氨酰胺酶（hTG2）是一种多功能酶。主要因其钙依赖性转氨活性而闻名，该活性导致在蛋白质表面上发现的谷氨酰胺和赖氨酸残基之间形成异肽键，但它也是GTP结合蛋白。过度表达和不受控制的hTG2活性已与许多人类疾病相关，包括癌症干细胞存活和转移表型。在本文中，我们基于我们先前报道的Cbz-Lys支架，提出了一系列靶向共价抑制剂（TCI）。从这项结构-活性关系（SAR）研究中，鉴定出了新型不可逆抑制剂，该抑制剂可阻断hTG2的转酰胺基化活性，并以高度的选择性和效率通过别构方式消除其与GTP的结合能力（kinact / K I > 10 5 M –1分钟–1）。还显示出一种优化的抑制剂（VA4）可以抑制表皮癌干细胞的侵袭，其EC 50为3.9μM，与我们先前报道的“命中” NC9相比有显着改善。
更新日期：2017-09-15
中文翻译：
消除人类组织转谷氨酰胺酶的转酰胺基作用和GTP结合活性的有效，靶向共价抑制剂的构效关系
人体组织转谷氨酰胺酶（hTG2）是一种多功能酶。主要因其钙依赖性转氨活性而闻名，该活性导致在蛋白质表面上发现的谷氨酰胺和赖氨酸残基之间形成异肽键，但它也是GTP结合蛋白。过度表达和不受控制的hTG2活性已与许多人类疾病相关，包括癌症干细胞存活和转移表型。在本文中，我们基于我们先前报道的Cbz-Lys支架，提出了一系列靶向共价抑制剂（TCI）。从这项结构-活性关系（SAR）研究中，鉴定出了新型不可逆抑制剂，该抑制剂可阻断hTG2的转酰胺基化活性，并以高度的选择性和效率通过别构方式消除其与GTP的结合能力（kinact / K I > 10 5 M –1分钟–1）。还显示出一种优化的抑制剂（VA4）可以抑制表皮癌干细胞的侵袭，其EC 50为3.9μM，与我们先前报道的“命中” NC9相比有显着改善。
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