Multikinase inhibitors are potent anticancer drugs that simultaneously intervene in
multiple related signaling cascades, thus being capable of blocking salvage pathways
that may play a role in the development of drug resistance. Multikinase inhibitors
are increasingly evaluated for indications other than cancer, but long-term safety
risks dictated by off-organ toxicities of these agents may prevent their safe and
effective use. Here, we describe a new approach in which platinum coordination chemistry
is applied for the development of a cell-selective multikinase inhibitor bioconjugate.
The platinum(II) kinase inhibitor bioconjugate was designed to be active with the
linker attached to the inhibitor and displayed improved activity by enhanced cell
specificity as well as enhanced intracellular retention, thereby prolonging its pharmacological
activity. In addition, the utilized platinum-based linkage technology potentiated
the inhibitory activity of the multikinase inhibitor. These features in combination
with carrier-mediated uptake in the target cells may revolutionize dosing regimens
and safety profiles of (multi)kinase inhibitors.
