A therapeutic patent overview of MDM2/X-targeted therapies (2014–2018)

ABSTRACT

Introduction: MDM2 and MDMX proteins provide the inhibition of p53 tumor suppressor, thus allowing for accelerated mutation-driven cancer microevolution. A pharmacological blockade of MDM2/X-p53 interaction results in p53 reactivation in p53^wt cells, leading to cancer growth inhibition. Throughout the past 20 years, multiple chemical entities have been proposed to reactivate p53 by antagonizing MDM2/X proteins.

Areas covered: This manuscript reviews 2014–2018 therapeutic patents in the field of MDM2/X antagonists and is a continuation of previous reviews on similar matter. The patents covering the use of MDM2/X antagonists in drug combinations are also presented in this review, as they constitute an important trend in the field of cancer treatment with MDM2/X antagonists.

Expert opinion: In the years 2014–2018, several previously-known chemical scaffolds have been further developed and disclosed. Importantly, in the same time period, many lead compounds have entered clinical trials for the treatment of cancer patients. Meanwhile, several important reports have pointed to serious limitations of anticancer properties of MDM2 antagonists. As a result, many efforts have been made to seek for positive, synergistic therapeutic effects of combined anti-cancer treatment strategies. One recent example is a dual targeting of MDM2 and additional protein targets by utilizing the PROTAC technology.

Trial registration: ClinicalTrials.gov identifier: NCT02264613.

Trial registration: ClinicalTrials.gov identifier: NCT02624986.

Trial registration: ClinicalTrials.gov identifier: NCT02670044.

Trial registration: ClinicalTrials.gov identifier: NCT02545283.

KEYWORDS:

• MDM2 antagonist
• MDMX antagonist
• p53
• PROTAC
• cancer
• small-molecule inhibitors
• protein-protein interaction
• clinical studies

Article highlights

• The liberation of p53 activity with MDM2 antagonists provides a non-genotoxic strategy for the treatment of p53-wild type tumors.

• The progress in the development of MDM2 antagonists patented between 2014 and 2018 is reviewed.

• The optimization of multiple chemical scaffolds has led to the discovery of low picomolar MDM2 antagonists.

• Several MDM2 antagonists are currently being evaluated in clinical trials.

• The limited activity of MDM2 antagonists justifies the need for the development of synergistic combined therapies.

• New PROTAC technology has been harnessed to target MDM2 protein for degradation, or to utilize its ubiquitinating properties for the elimination of other protein targets.

This box summarizes key points contained in the article.

Declaration of interest

L. Skalniak has received Sonata Grant No. UMO-2016/21/D/NZ7/00596 from the National Science Centre, Poland. T.A. Holak has received Symphony Grant No. UMO-2014/12/W/NZ1/00457 from the National Science Centre, Poland. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This research has been supported by the Sonata Grant No. UMO-2016/21/D/NZ7/00596 from the National Science Centre, Poland, and by the Symphony Grant No. UMO-2014/12/W/NZ1/00457 from the National Science Centre, Poland.