Ruthenium-based chemotherapeutics: are they ready for prime time?

Abstract

Since the discovery of cis-platinum, many transition metal complexes have been synthesized and assayed for antineoplastic activity. In recent years, ruthenium-based molecules have emerged as promising antitumor and antimetastatic agents with potential uses in platinum-resistant tumors or as alternatives to platinum. Ruthenium compounds theoretically possess unique biochemical features allowing them to accumulate preferentially in neoplastic tissues and to convert to their active state only after entering tumor cells. Intriguingly, some ruthenium agents show significant activity against cancer metastases but have minimal effects on primary tumors. Two ruthenium-based drugs, NAMI-A and KP1019, have reached human clinical testing. This review will highlight the chemical properties, mechanism of action, preclinical data, and early phase clinical results of these two lead ruthenium compounds. Other promising ruthenium agents will also be reviewed with emphasis on the novel ruthenium compound ONCO4417, and DW1/2 that has demonstrated Pim-1 kinase inhibition in preclinical systems. Further development of these and other ruthenium agents may rely on novel approaches including rational combination strategies as well as identification of potential pharmacodynamic biomarkers of drug activity aiding early phase clinical studies.

Fig. 1

Chemical structure of NAMI-A (Me = methyl group)

Fig. 2

Chemical structure of KP1019

Fig. 3

Chemical structures of two arene ruthenium(II) diamines

Fig. 4

Chemical structures of three ruthenium(II) arenes (RAPTA)

Fig. 5

Chemical structure of DW1, mimicking the protein kinase inhibitor staurosporine