Development of a Cell-Selective and Intrinsically Active Multikinase Inhibitor Bioconjugate
journal contributionposted on 20.04.2011, 00:00 authored by Stefan Harmsen, M. Emmy M. Dolman, Zoltan Nemes, Marie Lacombe, Bálint Szokol, János Pató, György Kéri, László Őrfi, Gert Storm, Wim E. Hennink, Robbert J. Kok
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.