Oligoethylene Phosphoramidate‐Based Kinase Inhibitor Prodrugs – Solubility, Enzyme Inhibition, and Hydrolysis

The efficiency of kinase inhibiting cancer therapeutics is often limited by their poor solubility in water. PEGylation is one possible strategy to improve the solubility of the drug, however, means to cleave off the PEG after reaching the target is important to make use of the therapeutic effects of the native drug. Moreover, the length of the PEG chains will have an effect on the solubility and binding. In this study, we want to extend our understanding of solubilizing oligo ethylene glycol (OEG) chains connected to kinase inhibitors using a pH labile phosphoramidate linker. We synthesize a library of drug-OEG conjugates for Ceritinib, Crizotinib, Palbociclib, and Ribocilib kinase inhibitors with n=2, 3, 4 and 8 OEG repeat units. We study the influence on water solubility, enzyme inhibition, and pH induced hydrolysis. A maximum in solubility is obtained for n=3 or 4. We show that small differences in chain length can strongly influence the water solubility, while all other properties remain relatively comparable.