Trends in Pharmacological Sciences
ReviewTargeting protein–protein interactions as an anticancer strategy
Section snippets
Rising interest in targeting PPIs
PPI interfaces represent a highly promising, although challenging, class of potential targets for therapeutic development [1]. In cancer, PPIs form signaling nodes and hubs that transmit pathophysiological cues along molecular networks to achieve an integrated biological output, thereby promoting tumorigenesis, tumor progression, invasion, and/or metastasis. Thus, pathway perturbation, through disruption of PPIs critical for cancer, offers a novel and effective strategy for curtailing the
PPI interfaces constitute basic units in oncogenic signaling networks
A variety of environmental, genetic, and epigenetic factors induce the reprogramming of cancer-initiating cells and the acquisition of physical and molecular features that promote tumorigenesis and provide resistance to therapeutics. These characteristics, including sustained proliferative signaling and evasion of growth suppressors, permit the development and progression of cancer and have been recognized as distinctive hallmarks of cancer (Figure 2) [2]. These hallmarks provide a molecular
Challenges in discovering PPI modulators
A number of challenges and concerns exist regarding targeting of PPIs, some of which include: (i) large PPI interface areas, (ii) a lack of deep pockets, (iii) the presence of noncontiguous binding sites, and (iv) a general lack of natural ligands. In addition, PPI surfaces differ from small-molecule binding sites in their shape and amino acid residue composition. In contrast to the well-defined and normally hydrophilic ligand-binding cavities observed in the crystal structures of enzymes and
Clinical validation of PPI targeting in cancer
Thousands of compounds have already been tested as potential inhibitors of various PPIs and the results are promising. Titrobifan, a glycoprotein IIb/IIIa inhibitor, and Maraviroc, an inhibitor of the CCR5–gp120 interaction, are currently available on the market as cardiovascular and anti-HIV drugs, respectively. These drugs demonstrate the feasibility of PPI targeting for the treatment of various diseases. In addition, several anticancer compounds have entered clinical trials, highlighting the
Emerging opportunities for targeting of PPIs
Although validated PPIs remain active targets for therapeutic development, new concepts and promising PPIs have emerged for anticancer drug discovery (Figure 2). For example, increased knowledge of cancer genomics and PPI-mediated epigenetic mechanisms and identification of cancer-specific onco-fusion proteins have revealed a large number of new PPIs that are directly associated with pathology of cancer. Recent insight into the consequences of various cancer therapeutics and the induced
Concluding remarks
Future efforts aimed at targeting of PPIs will be greatly accelerated by a number of recent advances. Understanding the nature of PPI interfaces and successful PPIMs may provide rationale design strategies for PPI-focused libraries. PPI assay technologies that closely reflect physiological conditions and address multiprotein complex issues are likely to shorten the process of lead discovery. PPI target discovery coupled with functional validation in genetically defined model systems is vital in
Acknowledgment
Work in our laboratory was supported in part by US National Institutes of Health grants P01CA116676 and U01 CA168449. F.R.K. and H.F. are Georgia Cancer Coalition Distinguished Scholars.
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