NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application

被引:590
作者
Trondl, Robert [1 ]
Heffeter, Petra [2 ,3 ,5 ]
Kowol, Christian R. [1 ,4 ]
Jakupec, Michael A. [1 ,4 ]
Berger, Walter [2 ,3 ,5 ]
Keppler, Bernhard K. [1 ,4 ]
机构
[1] Univ Vienna, Inst Inorgan Chem, A-1090 Vienna, Austria
[2] Med Univ Vienna, Inst Canc Res, A-1090 Vienna, Austria
[3] Med Univ Vienna, Ctr Comprehens Canc, A-1090 Vienna, Austria
[4] Univ Vienna, Res Platform Translat Canc Therapy Res, A-1090 Vienna, Austria
[5] Med Univ Vienna, Res Platform Translat Canc Therapy Res, A-1090 Vienna, Austria
关键词
IN-VITRO; PHASE-I; ANTITUMOR-ACTIVITY; OXIDATIVE STRESS; COMPLEX KP1019; NAMI-A; BINDING; CELL; COMPOUND; CYTOTOXICITY;
D O I
10.1039/c3sc53243g
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
NKP-1339 is the first-in-class ruthenium-based anticancer drug in clinical development against solid cancer and has recently been studied successfully in a phase I clinical trial. Ruthenium compounds such as KP1019 (indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) and NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) have a high tumour targeting potential based (1) on their strong binding to serum proteins such as albumin and transferrin as well as (2) on their activation in the reductive tumour milieu. The redox activity of ruthenium compounds is believed to represent one major mode of action leading to disturbance of the cellular redox balance and, consequently, induction of G(2)/M cell cycle arrest, blockage of DNA synthesis, and induction of apoptosis via the mitochondrial pathway. Moreover, potent synergistic activities of NKP-1339 with the clinically approved tyrosine kinase inhibitor sorafenib were recently reported in vitro and in vivo. Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.
引用
收藏
页码:2925 / 2932
页数:8
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