Design and Characterization of a Pyridone-Containing EZH2 Inhibitor Phosphate Prodrug.

A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound ) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound ) to animals following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound . In separate experiments, the prodrug demonstrated impressive tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures .