Proteomics for cancer drug design

ABSTRACT

Introduction: Signal transduction cascades drive cellular proliferation, apoptosis, immune, and survival pathways. Proteins have emerged as actionable drug targets because they are often dysregulated in cancer, due to underlying genetic mutations, or dysregulated signaling pathways. Cancer drug development relies on proteomic technologies to identify potential biomarkers, mechanisms-of-action, and to identify protein binding hot spots.

Areas covered: Brief summaries of proteomic technologies for drug discovery include mass spectrometry, reverse phase protein arrays, chemoproteomics, and fragment based screening. Protein-protein interface mapping is presented as a promising method for peptide therapeutic development. The topic of biosimilar therapeutics is presented as an opportunity to apply proteomic technologies to this new class of cancer drug.

Expert opinion: Proteomic technologies are indispensable for drug discovery. A suite of technologies including mass spectrometry, reverse phase protein arrays, and protein-protein interaction mapping provide complimentary information for drug development. These assays have matured into well controlled, robust technologies. Recent regulatory approval of biosimilar therapeutics provides another opportunity to decipher the molecular nuances of their unique mechanisms of action. The ability to identify previously hidden protein hot spots is expanding the gamut of potential drug targets. Proteomic profiling permits lead compound evaluation beyond the one drug, one target paradigm.

KEYWORDS:

• Biosimilar
• drug discovery
• hot spot
• mass spectrometry
• peptide
• protein-protein interaction
• reverse phase protein array
• validation
• cancer

Article highlights

• Proteomic profiling and quantification by mass spectrometry and reverse phase protein arrays yield mechanism-of-action information and phenotypic hits to advance lead compound evaluation beyond the one drug, one target paradigm. Chemoproteomics provides a method for determining specificity for enzymes with similar catalytic domains or isoforms within the same enzyme family.

• Protein-protein interaction mapping via chemoproteomics, fragment based screening, and protein painting are essential for identifying small peptide inhibitors/activators that may be the next generation of cancer therapeutics.

• The development of protein-protein interaction inhibitors could be advanced by (a) improving methods to more rapidly identify hotspot residues of protein-protein interactions in native protein complexes, (b) increasing development of small molecule moieties suited to selectively target protein-protein interactions, and (c) improving the bioavailability and stability of peptides and peptidomimetic drugs for intracellular delivery.

• Therapeutic target validation requires three assessments of the drug target: (1) detection of the drug target in diseased tissue (cells), using a method that is sensitive and specific to quantify an increase/decrease in the drug target; (2) assays to prove that the target was inhibited/activated; and (3) correlation between drug target modulation and clinical outcome.

• Characterizing biosimilar therapeutics should entail a critical investigation into whether differences between the bio-original structure and a biosimilar are clinically meaningful and create differences in efficacy or toxicity.

• The goals of protein-protein interaction mapping are to: (a) increase experimental knowledge of structure-function based techniques, (b) allow better prediction of interaction sites in protein complexes, (c) provide confirmation of recombinant and/or biosimilar protein binding sites, and (d) provide structural information necessary for creating bio-functional therapeutics.

Acknowledgments

The authors would like to thank Lance Liotta for editorial advice.

Declaration of interest

A.Haymond, J.Davis, and V. Espina receive salary support from NIH Innovative Molecular Analysis Technologies (IMAT) grant 1R33CA20693701.

A. Haymond receives salary support from National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR068436-03 and Center for Innovative Technologies (CIT) CRCF Award MF18-007-LS. A. Haymond has stock ownership and is a consultant for Monet Pharmaceuticals.

V. Espina is an inventor of the protein painting technology and, as a university employee, is entitled to receive patent royalties per university policies. V. Espina is a consultant for Avant Diagnostics.

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported in part by George Mason University, and the National Institutes of Health Innovative Molecular Analysis Technologies (IMAT) program grant 1R33CA20693701, ‘Protein painting identifies therapeutic targets at protein-protein interfaces’ and the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR068436 ‘Probes to Target the 3-way Hotspot of IL1RacP to Abolish Aberrant Interleukin Inflammation’ (to Lance Liotta).