Initial evaluation of the antitumour activity of KGP94, a functionalized benzophenone thiosemicarbazone inhibitor of cathepsin L
Initial evaluation of the antitumour activity of KGP94, a functionalized benzophenone thiosemicarbazone inhibitor of cathepsin L
复制标题
DOI：
10.1016/j.ejmech.2012.10.039
复制
发表时间：
2012-12-01
影响因子：
6.7
通讯作者：
Trawick, Mary Lynn
中科院分区：
文献类型：
--
作者：
Chavarria, Gustavo E.;Horsman, Michael R.;Trawick, Mary Lynn
KGP94（一种来自功能化二苯甲酮缩氨基硫脲衍生物特权库的先导化合物）对组织蛋白酶 L 的抑制模式的动力学分析表明，KGP94 是该酶的时间依赖性、可逆性和竞争性抑制剂。这些结果与瞬时共价键的形成一致，并得到分子模型的支持，该模型将抑制剂的硫代羰基置于酶活性位点 Cys25 的硫醇盐部分附近。 KGP94 显着降低组织蛋白酶 L 对人 I 型胶原的活性，并阻止 MDA-MB-231 人乳腺癌细胞的迁移和侵袭。使用 C3H 小鼠乳腺癌模型，在体内实现了针对最近植入和建立的肿瘤的生长迟缓。 (C) 2012 Elsevier Masson SAS。版权所有。
Kinetic analysis of the mode of inhibition of cathepsin L by KGP94, a lead compound from a privileged library of functionalized benzophenone thiosemicarbazone derivatives, demonstrated that it is a time-dependent, reversible, and competitive inhibitor of the enzyme. These results are consistent with the formation of a transient covalent bond, and are supported by molecular modeling that places the thiocarbonyl of the inhibitor in proximity to the thiolate moiety of the enzyme active site Cys25. KGP94 significantly decreased the activity of cathepsin L toward human type I collagen, and impeded both migration and invasion of MDA-MB-231 human breast cancer cells. Growth retardation was achieved in vivo against both recently implanted and established tumours using a C3H mouse mammary carcinoma model. (C) 2012 Elsevier Masson SAS. All rights reserved.