6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer.
6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer.
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DOI：
10.1021/acs.jmedchem.8b00838
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发表时间：
2018-09-27
影响因子：
7.3
通讯作者：
Kelso MJ
中科院分区：
文献类型：
--
作者：
Buckley BJ;Aboelela A;Minaei E;Jiang LX;Xu Z;Ali U;Fildes K;Cheung CY;Cook SM;Johnson DC;Bachovchin DA;Cook GM;Apte M;Huang M;Ranson M;Kelso MJ
转移是大多数(~90%)恶性肿瘤的死亡原因。据报道，口服节钾利尿剂阿米洛利及其5-N，N-六亚甲基阿米洛利(HMA)在多种体外和动物模型中显示出强大的抗肿瘤/转移作用。这些作用可能至少部分是由于抑制尿激酶型纤溶酶原激活物(UPA)，尿激酶型纤溶酶原激活物(UPA)是细胞侵袭和转移的关键蛋白酶决定因素。这项研究报告了6-取代HMA类似物的发现，它们显示出对uPA的纳摩尔效力，对相关的胰酶样丝氨酸蛋白酶的高选择性，以及对阿米洛利利尿剂和抗钾尿剂靶点上皮钠通道(ENaC)的最小抑制作用。两个类似物在晚期实验性小鼠转移模型中被证明减少了肺转移，一个类似物在胰腺癌原位移植小鼠模型中完全抑制了肝转移的形成。这些结果支持进一步评价6-取代HMA衍生物作为uPA靶向抗癌药物的作用。
Metastasis is the cause of death in the majority (~90%) of malignant cancers. The oral potassium-sparing diuretic amiloride and its 5-substituted derivative 5-N,N-(hexamethylene)amiloride (HMA) reportedly show robust antitumor/ metastasis effects in multiple in vitro and animal models. These effects are likely due, at least in part, to inhibition of the urokinase plasminogen activator (uPA), a key protease determinant of cell invasiveness and metastasis. This study reports the discovery of 6-substituted HMA analogs that show nanomolar potency against uPA, high selectivity over related trypsin-like serine proteases, and minimal inhibitory effects against epithelial sodium channels (ENaC), the diuretic and antikaliuretic target of amiloride. Reductions in lung metastases were demonstrated for two analogs in a late-stage experimental mouse metastasis model, and one analog completely inhibited formation of liver metastases in an orthotopic xenograft mouse model of pancreatic cancer. The results support further evaluation of 6-substituted HMA derivatives as uPA-targeting anticancer drugs.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1016/j.urolonc.2014.12.001
发表时间：
2015-04-01
影响因子：
2.7
作者：
Dohn, Line Hammer;Illemann, Martin;Laerum, Ole D.
通讯作者：
Laerum, Ole D.
DOI：
10.3109/10799899109064686
发表时间：
1991-01-01
期刊：
JOURNAL OF RECEPTOR RESEARCH
影响因子：
--
作者：
GARRITSEN, A;IJZERMAN, AP;SOUDIJN, W
通讯作者：
SOUDIJN, W
影响因子：
3.5
作者：
Cochran BJ;Gunawardhana LP;Vine KL;Lee JA;Lobov S;Ranson M
通讯作者：
Ranson M
影响因子：
--
作者：
Brungs D;Chen J;Aghmesheh M;Vine KL;Becker TM;Carolan MG;Ranson M
通讯作者：
Ranson M