Increased ribosome synthesis is essential for cancer cells to keep up with the demands of rapid proliferation. Targeting ribosome biogenesis has become an attractive strategy in anticancer drug development as a result. Thus far, only Platinum(Pt)-based compounds are the only coordination complexes have been reported to induce ribosome biogenesis stress. Unfortunately, Pt therapeutics rely heavily on organic cation transporters and copper transporter 1 for uptake. Inactivation from free thiols is another downside of Pt(II) agents. Ruthenium(Ru) polypyridyl compounds have been developed as alternatives to Pt(II) due to resistance to thiol-mediated inactivation and increased cellular uptake. We utilized these properties of Ru(II) to develop a potent scaffold which induced ribosome biogenesis stress. Nucleophosmin delocalized from the nucleolus, a key phenotypic marker in ribosome biogenesis stress, following treatment with our active scaffold was observed. Additionally, a COMPARE analysis through the NCI 60-cell line panel showed our compound’s resistance-sensitivity profile correlated best to actinomycin D, which is known to induce ribosome biogenesis stress. Additionally, some other small molecules induce ribosome biogenesis stress as a pleiotropic effect of their primary mechanism. We show that this Ru(II) scaffold induces ribosome stress directly. Our scaffold was resistant to reaction with free thiols and did not possess toxic behavior <i>in vivo</i>, making it a promising scaffold for future ribosome biogenesis-targeting Ru(II) agents.

Polypyridyl Ru(II) scaffold induces ribosome biogenesis stress

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