MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present)

Abstract

Background: Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer therapy. Objective: This updated patent review is an attempt to compile the research and achievements of the various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most relevant patents which have recently appeared in the literature. Methods: Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective compounds which are or were examined in clinical trials. Results: Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types of cancer or non-cancer diseases. A great number of patents and research work around new MDM2- p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years prove that this targeted therapy is in the scope of interest for many business and academic research groups. Conclusion: Novel MDM2 inhibitors thanks to higher potency and better ADME properties have shown effectiveness in preclinical and clinical development however the final improvement of therapeutic potential for MDM2 inhibitors might depend on the useful combination therapy and exploring new cancer and non-cancer indications.

Tumor suppressing role of serum-derived exosomal microRNA-15a in osteosarcoma cells through the GATA binding protein 2/murine double minute 2 axis and the p53 signaling pathway

“…In tumor cells, overexpression of MDM2 is a major contributor to p53 degradation, in addition to mutation or deletion of the TP53 gene [ 39 ]. Therefore, blocking the interaction between MDM2 and p53 or suppressing MDM2 may serve as a therapeutic strategy for cancer treatment [ 40 , 41 ]. In this study, a binding relationship between GATA2 and the promoter region of MDM2 was validated, and a positive correlation between GATA2 and MDM2 was confirmed in the OS samples.…”

Down-regulated MicroRNAs in Gastric Carcinoma May Be Targets for Therapeutic Intervention and Replacement Therapy

“…Proteolysis targeting chimeras (PROTACS) directed against intrinsically disordered regions of transcription factors with Cys-reactive inhibitors and another moiety engaging an E3 ubiquitin ligase are emerging agents for interference (194). The druggability of small GTPase related molecules, GEFs and GAPs has to be categorized as critical, despite of encouraging recent developments (195,196) (197)(198)(199).…”

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

“…Thus, the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer via the restoration of WTp53 function. Indeed, a compilation of patents on small molecule MDM2 inhibitors has been recently published [24] and a critical discussion on the biological rationale of these strategies have also been conducted [23,95].…”

“…In this sense, numerous tumor suppressor approaches are related to p53-MDM2/MDMX, namely preventing the formation of p53-MDM2 complexes, preventing the p53 protein ubiquitination degradation and modifying p53 transcriptional active region to stabilize the p53 protein [19][20][21][22]. It is important to mention that comprehensive literature reviews on the rationale of using small molecules and peptide that function as MDMX inhibitors or as dual MDM2/MDMX inhibitors have been recently published [23,24].Other approaches for the reactivation of p53 have also been successful, for instance the inhibition of the nuclear export factor CRM-1 [25]. Another viable approach for the activation of p53 is the inhibition of casein kinase 1A1 (CKIa) [26,27], as well as of the sirtuins SirT1 and SirT2, which are implicated in a series of essential cellular processes and disease conditions [28].…”

“…In this sense, numerous tumor suppressor approaches are related to p53-MDM2/MDMX, namely preventing the formation of p53-MDM2 complexes, preventing the p53 protein ubiquitination degradation and modifying p53 transcriptional active region to stabilize the p53 protein [19][20][21][22]. It is important to mention that comprehensive literature reviews on the rationale of using small molecules and peptide that function as MDMX inhibitors or as dual MDM2/MDMX inhibitors have been recently published [23,24].…”