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Review
. 2013 Jul;34(7):393-400.
doi: 10.1016/j.tips.2013.04.007. Epub 2013 May 29.

Targeting protein-protein interactions as an anticancer strategy

Andrei A Ivanov  1 , Fadlo R Khuri, Haian Fu
Affiliations
Review

Targeting protein-protein interactions as an anticancer strategy

Andrei A Ivanov et al. Trends Pharmacol Sci. 2013 Jul.

Abstract

The emergence and convergence of cancer genomics, targeted therapies, and network oncology have significantly expanded the landscape of protein-protein interaction (PPI) networks in cancer for therapeutic discovery. Extensive biological and clinical investigations have led to the identification of protein interaction hubs and nodes that are critical for the acquisition and maintenance of characteristics of cancer essential for cell transformation. Such cancer-enabling PPIs have become promising therapeutic targets. With technological advances in PPI modulator discovery and validation of PPI-targeting agents in clinical settings, targeting of PPI interfaces as an anticancer strategy has become a reality. Future research directed at genomics-based PPI target discovery, PPI interface characterization, PPI-focused chemical library design, and patient-genomic subpopulation-driven clinical studies is expected to accelerate the development of the next generation of PPI-based anticancer agents for personalized precision medicine. Here we briefly review prominent PPIs that mediate cancer-acquired properties, highlight recognized challenges and promising clinical results in targeting PPIs, and outline emerging opportunities.

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Figures

Figure 1
Figure 1. Rising number of Publications in the field of cancer-related PPIs
PubMed database was searched with the following keywords: protein-protein interaction, tumor, cancer, and inflammation.
Figure 2
Figure 2. Representative PPIs in oncogenic signaling networks that drive the acquisition and development of hallmarks of cancer
Grey dotted arrows connect PPIs with corresponding cancer hallmarks. Some PPIs contribute to multiple features of cancer. It is cautioned that some PPIs may impact global processes of cell growth and their precise connections to cancer remain to be established.
Figure 3
Figure 3. Examples of PPI inhibitors entered clinical trials and emerging agents
Inhibitors of MDM2/p53, Bcl2, XIAP, and Hsp90 PPIs are in Phase 1-3. Examples of promising PPI targets with recently identified novel inhibitors include MLL1/WDR5, β-Catenin/TCF, BCLAF1/L3MBTL3, BRD4/Histone H4, and 14-3-3 interactions. Chemical structures of representative inhibitors are shown along with available crystal structures of protein-protein complexes. Shown in details are: a superimposition of Bak peptide (orange, carbon atoms are colored cyan) and ABT-737 (carbon atoms are colored green) bound at BCL-XL (PDB ID: 1BXL, 2YXJ). ABT-737 occupies the same hydrophobic pocket on Bcl-XL surface as the peptide, overlapping with Leu78 and Ile85 Bak residues critical for the peptide binding (top-left); a crystal structure of Hsp90 in a complex with Geldanamycin (PDB ID: 1YET), the first Hsp90 inhibitor entered clinical trials (top-right); a superimposition of p53 peptide and Nutline-2 (one of the first identified potent MDM2/p53 inhibitors) bound to N-terminal domain of MDM2 (PDB ID: 1YCR, 1RV1). Phe19, Trp23, and Leu26 residues of p53 peptide occupy hydrophobic pocket of MDM2. The ethoxy- and chlorophenyl groups of Nutlin-2 match the positions of Phe19, Trp23, and Leu26, respectively (bottom-right); a superimposition of SMAC AVPI peptide (the carbon atoms are colored orange) and GDC-0152 the first SMAC mimetic entered clinical trials (the carbon atoms colored green) (bottom-left, PDB ID: 3UW5, 1G73). The molecular surfaces of Hsp90, Bcl-XL, MDM2, and XIAP are colored by electrostatic potential (blue – positive, white – neutral, red – negative).
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