A concise review on MDM2 inhibitors and recent progress in radiopharmaceutical development for imaging MDM2 expression in tumors with PET or SPECT

Abstract

Murine double minute 2 (MDM2, also known as human double minute 2 or HDM2) is a negative regulator of the tumor suppressor protein p53 and is overexpressed in many cancers. Over the past two decades, substantial progress has been made in developing inhibitors of the MDM2-p53 interaction, thereby allowing the p53 protein to exert antitumor effects through cell apoptosis and cycle arrest. While there are currently no FDA-approved MDM2 inhibitors available, several small molecule MDM2 inhibitors and a stapled peptide inhibitor of the MDM2-p53 interaction are in clinical development. Availability of these clinical candidates, representing a diverse array of chemical scaffolds that bind to the same p53 binding site on the MDM2 protein with low nanomolar inhibition potency (IC₅₀), presents a significant opportunity for developing molecular imaging probes for MDM2 in parallel. This review summarizes the MDM2 inhibitors that have been evaluated in clinical trials, which could serve as starting leads for imaging probe development, and recent progress in developing radiotracers for MDM2 and for evaluating MDM2 expression levels in tumors noninvasively using the highly sensitive, molecular imaging techniques positron emission tomography (PET) or single-photon emission computed tomography (SPECT).