Hovhannes (Hovik) Gukasyan, PhD, is an associate professor of pharmacology and pharmaceutical sciences, and is helping grow the school’s undergraduate major in biopharmaceutical sciences. He spent two decades in the pharmaceutical industry, including roles at Pfizer and AbbVie, and served as an adjunct professor at USC Mann and Keck Graduate Institute School of Pharmacy and Health Sciences. He earned a PhD in pharmaceutical sciences from USC Mann.
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 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo 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 in vivo.