Protein-protein interaction inhibitors: advances in anticancer drug design

ABSTRACT

Introduction: Pocket-based drug design has contributed to major scientific breakthroughs in pharmaceutical research and development (R&D). The integrated use of experimental and computational methods, primarily during the early phases of drug discovery, has enabled the development of highly potent and selective small-molecule ligands. In this scenario, the targeting of protein-protein interactions (PPIs) has emerged as an attractive strategy for designing innovative drugs for highly complex diseases, such as cancer.

Areas covered: This article focuses on the use of experimental and computational approaches with a diversity of PPI classes and discusses the relevant advances in the field, primarily for oncological applications. Analyses of the target binding pockets and medicinal chemistry approaches used to develop promising PPI inhibitors are provided, with an emphasis on data reported over the past 2 years.

Expert opinion: PPI drug discovery is a challenging field that depends completely on accurate structural data. The integration of molecular docking, nuclear magnetic resonance and X-ray crystallography is a cornerstone for the current development of effective PPI inhibitors. Although this field has not reached its peak, several compounds have entered clinical trials over the past few years, providing promising perspectives for novel therapies for highly prevalent and life-threatening conditions.

KEYWORDS:

• Structure-based drug design
• protein-protein interactions
• X-ray crystallography
• molecular docking
• hot spots
• cancer

Article highlights

• Understanding the mechanisms of ligand-receptor recognition is a key component in the current context of pharmaceutical research and development (R&D).

• Protein-protein interactions (PPIs) are highly coordinated biological processes that are pivotal for cell reproduction, communication and homeostasis. The deregulation of these networks is associated with the emergence of severe diseases, such as cancer.

• PPIs are considered to be challenging drug targets because of the specific features of their binding surfaces.

• The targeting of PPIs is an evolving field that has been actively pursued by the key players in drug R&D.

• Current structure-based approaches to PPI drug discovery have contributed to the development of several compounds that have reached clinical development.

This box summarizes key points contained in the article.

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

The authors gratefully acknowledge the financial support of the State of Sao Paulo Research Foundation (FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo), grants 2013/07600-3 (CEPID-CIBFar) and 2013/25658-9, and the National Council for Scientific and Technological Development (CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico), Brazil.