An update patent review of MDM2-p53 interaction inhibitors (2019-2023).

Introduction: The activity of the major tumor suppressor protein p53 is disrupted in nearly all human cancer types, either by mutations in TP53 gene or by overexpression of its negative regulator, Mouse Double Minute 2 (MDM2). The release of p53 from MDM2 and its homolog MDM4 with inhibitors based on different chemistries opened up a prospect for a broad, non-genotoxic anticancer therapy.

Areas Covered: This article reviews the patents and patent applications between years 2019 and 2023 in the field of MDM2-p53 interaction inhibitors. The newly reported molecules searched in Espacenet, Google Patents, and PubMed were grouped into five general categories: compounds having single-ring, multi-ring, or spiro-oxindole scaffolds, peptide derivatives, and proteolysis-targeting chimeras (PROTACs). The article also presents the progress of MDM2 antagonists of various structures in recruiting or completed cancer clinical trials.

Expert Opinion: Despite 20 years of intensive studies after the discovery of the first-in-class small-molecule inhibitor, Nutlin-3, no drugs targeting MDM2-p53 interaction have reached the market. Nevertheless, more than 10 compounds are still being evaluated in clinics, both as standalone drugs and in combinations with other targeted therapies or standard chemotherapy agents, including two inhibitors in phase 3 studies and two compounds granted orphan-drug/fast-track designation by the FDA.