FOLICation: Engineering approved drugs as potential p53–MDM2 interaction inhibitors for cancer therapy

Abstract

Cancer is characterized by uncontrolled growth of abnormal cells leading to the formation of tumors. Normally, the pro-apoptotic p53 protein plays a central role in protecting cells against carcinogenesis. In almost 50% human tumor cells, however, the p53 protein is dysregulated by direct interaction with its negative regulator, the Murine Double Minute 2 (MDM2) protein. Therefore, blocking the p53-binding pocket on MDM2, leading to the activation of tumor suppressor p53 presents a novel therapeutic strategy against several types of cancers. The published crystal structure of MDM2 bound with the p53 binding domain has revealed that three key hydrophobic residues of p53 are buried deep into the binding cavity of MDM2 and thus are central to p53–MDM2 binding. Accordingly, several low-molecular-weight compounds have been developed that mimic these three hydrophobic residues and thus bind to the MDM2 pocket, leading in turn to inhibition of the deleterious p53–MDM2 interaction. It is noteworthy that these inhibitors also possess an additional hydrophilic group that is shown to be necessary as a “cover” protecting the hydrophobic interaction surface between inhibitor and MDM2 from surrounding solvent. In comparison, several FDA-approved drugs possess the three key hydrophobic features necessary for binding to MDM2, but lack the fourth hydrophilic moiety, thus possibly hindering their ability as potential p53–MDM2 interaction inhibitors. Therefore, we hypothesize that conjugation of hydrophilic vitamin folic acid or its analogs to these drugs (termed “FOLICation”) may provide them with the much-needed hydrophilic cover and make them suitable for investigation as potentially novel p53–MDM2 inhibitors. We also anticipate that FOLICation of these drugs may further lead to their enhanced and selective uptake by cancer cells, owing to the significantly higher expression of folic acid receptors on cancer cells compared to normal cells.