Review
Targeting protein–protein interactions as an anticancer strategy

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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.

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.

References (91)

  • D.H. Tsao

    Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design

    Bioorg. Med. Chem.

    (2006)
  • T. Miura

    Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design

    Bioorg. Med. Chem. Lett.

    (2011)
  • A. Suda

    Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors

    Bioorg. Med. Chem. Lett.

    (2012)
  • S.Y. Yang

    Pharmacophore modeling and applications in drug discovery: challenges and recent advances

    Drug Discov. Today

    (2010)
  • V. Corradi

    Computational techniques are valuable tools for the discovery of protein–protein interaction inhibitors: the 14-3-3sigma case

    Bioorg. Med. Chem. Lett.

    (2011)
  • H.R. Lawrence

    Identification of a disruptor of the MDM2-p53 protein–protein interaction facilitated by high-throughput in silico docking

    Bioorg. Med. Chem. Lett.

    (2009)
  • X. Wang et al.

    Mdm2 and MdmX partner to regulate p53

    FEBS Lett.

    (2012)
  • M. Andreeff

    A multi-center, open-label, Phase I study of single agent RG7112, a first in class p53–MDM2 antagonist, in patients with relapsed/refractory acute myeloid and lymphoid leukemias (AML/ALL) and refractory chronic lymphocytic leukemia/small cell lymphocytic lymphomas (CLL/SCLL)

    Blood

    (2010)
  • P.K. Paik

    A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer

    Lung Cancer

    (2011)
  • J.R. Porter

    Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy

    Curr. Opin. Chem. Biol.

    (2010)
  • L.A. Garraway et al.

    Lessons from the cancer genome

    Cell

    (2013)
  • J.E. Delmore

    BET bromodomain inhibition as a therapeutic strategy to target c-Myc

    Cell

    (2011)
  • S.R. Daigle

    Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor

    Cancer Cell

    (2011)
  • J.A. Wells et al.

    Reaching for high-hanging fruit in drug discovery at protein-protein interfaces

    Nature

    (2007)
  • B.T. Hennessy

    Exploiting the PI3K/AKT pathway for cancer drug discovery

    Nat. Rev. Drug Discov.

    (2005)
  • E.V. Prochownik et al.

    Therapeutic targeting of Myc

    Genes Cancer

    (2010)
  • M.C. Puckett

    Integration of the apoptosis signal-regulating kinase 1-mediated stress signaling with the Akt/PKB-IkappaB kinase cascade

    Mol. Cell. Biol.

    (2013)
  • T.K. Kelly

    Epigenetic modifications as therapeutic targets

    Nat. Biotechnol.

    (2010)
  • P. Buchwald

    Small-molecule protein–protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations

    IUBMB Life

    (2010)
  • I.S. Moreira

    Hot spots – a review of the protein–protein interface determinant amino-acid residues

    Proteins

    (2007)
  • N. Watanabe et al.

    Phosphorylation-dependent protein-protein interaction modules as potential molecular targets for cancer therapy

    Curr. Drug Targets

    (2012)
  • S. Muller et al.

    Epigenetic chemical probes

    Clin. Pharmacol. Ther.

    (2012)
  • H. Fu

    14-3-3 proteins: structure, function, and regulation

    Annu. Rev. Pharmacol. Toxicol.

    (2000)
  • A. Barker

    Expanding medicinal chemistry space

    Drug Discov. Today

    (2012)
  • J.M. Mason

    Design and development of peptides and peptide mimetics as antagonists for therapeutic intervention

    Future Med. Chem.

    (2010)
  • C. Billard

    Design of novel BH3 mimetics for the treatment of chronic lymphocytic leukemia

    Leukemia

    (2012)
  • J.A. Flygare

    Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152)

    J. Med. Chem.

    (2012)
  • P.J. Houghton

    Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program

    Pediatr. Blood Cancer

    (2012)
  • Y. Rew

    Structure-based design of novel inhibitors of the MDM2-p53 interaction

    J. Med. Chem.

    (2012)
  • R.E. Moellering

    Direct inhibition of the NOTCH transcription factor complex

    Nature

    (2009)
  • M. Rubinstein et al.

    Peptidic modulators of protein–protein interactions: progress and challenges in computational design

    Biopolymers

    (2009)
  • A. Rothe

    In vitro display technologies reveal novel biopharmaceutics

    FASEB J.

    (2006)
  • L.R. Whitby et al.

    Comprehensive peptidomimetic libraries targeting protein-protein interactions

    Acc. Chem. Res.

    (2012)
  • C.J. Brown

    Stapled peptides with improved potency and specificity that activate p53

    ACS Chem. Biol.

    (2013)
  • S.A. Kawamoto

    Design of triazole-stapled BCL9 alpha-helical peptides to target the beta-catenin/B-cell CLL/lymphoma 9 (BCL9) protein–protein interaction

    J. Med. Chem.

    (2012)
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