title: Development of a cell-selective and intrinsically active multikinase inhibitor bioconjugate.
abstract: 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.
authors: Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors: Stefan
authors: S
authors: Harmsen
authors: M Emmy M
authors: ME
authors: Dolman
authors: Zoltan
authors: Z
authors: Nemes
authors: Marie
authors: M
authors: Lacombe
authors: Bálint
authors: B
authors: Szokol
authors: János
authors: J
authors: Pató
authors: György
authors: G
authors: Kéri
authors: László
authors: L
authors: Orfi
authors: Gert
authors: G
authors: Storm
authors: Wim E
authors: WE
authors: Hennink
authors: Robbert J
authors: RJ
authors: Kok
mesh_terms: D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009113:Muramidase / Q000737:chemistry* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D056831:Coordination Complexes; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D009113:Muramidase