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

Area of Science:

• Oncology
• Medicinal Chemistry
• Drug Discovery

Background:

• The tumor suppressor protein p53 is crucial for preventing cancer but is often inactivated by Mouse Double Minute 2 (MDM2) or MDM4.
• Targeting the MDM2-p53 interaction offers a non-genotoxic therapeutic strategy for various human cancers.

Purpose of the Study:

• To review patents and patent applications from 2019-2023 concerning inhibitors of the MDM2-p53 interaction.
• To categorize novel molecules and assess their clinical trial progress.

Main Methods:

• Comprehensive literature search of Espacenet, Google Patents, and PubMed for relevant patents.
• Classification of identified inhibitors into five structural categories: single-ring, multi-ring, spiro-oxindole scaffolds, peptide derivatives, and PROTACs.
• Analysis of clinical trial status for compounds targeting the MDM2-p53 pathway.

Main Results:

• The review identified diverse chemical scaffolds for MDM2-p53 inhibitors, including novel single-ring, multi-ring, spiro-oxindole, peptide, and PROTAC-based compounds.
• Despite extensive research since Nutlin-3's discovery, no MDM2-p53 inhibitors have gained market approval.
• Over 10 compounds are in clinical development, with some in Phase 3 trials and others granted FDA orphan-drug/fast-track designation.

Conclusions:

• The field of MDM2-p53 inhibitors continues to advance, with ongoing clinical evaluation of multiple drug candidates.
• Despite challenges, the development of these inhibitors holds significant promise for novel, non-genotoxic anticancer therapies.