A therapeutic patent overview of MDM2/X-targeted therapies (2014–2018). (4th March 2019)

• Record Type: Journal Article
• Authors: Skalniak, Lukasz; Surmiak, Ewa; Holak, Tad A.
• Is Part Of: Expert opinion on therapeutic patents. Volume 29:Number 3(2019)
• Page Start: 151
• Page End: 170
• Publication Date: 2019-03-04
• Subjects: MDM2 antagonist -- MDMX antagonist -- p53 -- PROTAC -- cancer -- small-molecule inhibitors -- protein-protein interaction -- clinical studies; Drugs -- Patents -- Periodicals; 615.10272
• DOI: 10.1080/13543776.2019.1582645
• Languages: English
• ISSNs: 1354-3776

Abstract

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.