Peptides and peptidomimetics in the p53/MDM2/MDM4 circuitry - a patent review

ABSTRACT

Introduction: Restoration of the p53 tumor suppressor function is an attractive anticancer strategy. Despite the development of several therapeutics targeting the two main p53 negative regulators, MDM2 and MDM4, no one has yet reached clinical application. In the past, several efforts have been employed to develop more specific and efficient compounds that can improve and/or overcome some of the features related to small molecule compounds (SMC). Peptides and peptidomimetics are emerging as attractive molecules given their increased selectivity, reduced toxicity and reduced tendency to develop tumor-resistance compared to SMC.

Area covered: This article reviews publications and patents (publicly available up to April 2016) for peptides and derivatives aimed to reactivate the oncosuppressive function of p53, with a particular focus on inhibitors of MDM2/MDM4. Emphasis is placed on the efficacy of these compounds compared to the p53-reactivating small molecules developed so far.

Expert opinion: A number of promising peptides for p53 reactivation in cancer therapy have been developed. These compounds appear to possess improved features compared to SMC, especially for their ability to simultaneously target the MDM2/MDM4 inhibitors, and their increased specificity.

KEYWORDS:

• p53 reactivation therapy
• anticancer peptide
• MDM2
• MDM4
• MDMX
• dual-inhibitor
• therapy-resistance

Article highlights

• Despite the numerous efforts targeting the re-activation of p53 oncosuppressive function, no one of these drugs has yet reached the clinical market.

• In the last ten years, many peptide-based therapeutics have been developed in this field, targeting both p53 (in its wild-type or mutant forms) or targeting the two critical p53-inhibitors MDM2 and MDM4.

• Many of these peptide compounds have shown the ability to target simultaneously MDM2 and MDM4, improving their therapeutic efficacy.

• One of these peptide-based therapeutics is able to target mutant MDM2 proteins originated in SMC-resistant tumors, providing increased effectiveness.

• Peptide-therapeutics have provided the possibility to target different p53/MDM2/MDM4 regions characterized by flat un-druggable surfaces, demonstrating high efficiency and reduced toxicity compared to other entities.

This box summarizes key points contained in the article.

Acknowledgments

The authors apologize for the inability to cite many important studies due to space limitations.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

F. Moretti is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC IG-12767), and Project ‘FaReBio di Qualita’ from Italian Ministry of Economy and Finance to the CNR. R. Lucà is supported by FIRC fellowship (N. 18153) ‘Edvige e Mario Gervasini’.