Elucidating Compound Selectivity: Integration of Chemoproteomic, Protein Signaling, and Gene Expression Profiles
Scott E. Warder, Shaun M. McLoughlin, Paul L. Richardson, Joseph L. Meuth, Paul Mark Jung, Robert D. Hubbard, T. Matt Hansen, Donna Oksenberg, Jane E. Lamerdin, Michael J. Liguori, Jieyi Wang, Randy L Bell, Steven K. Davidsen, John K. Westwick, JOHN C. ROGERS, Eric A.G. Blomme · The FASEB Journal · 2009
Compound profiling technologies that enable an early assessment of cellular effects related to toxicology and pharmacology can contribute to a reduction of late stage failures in drug development. However, the implementation of ‐omic profiling strategies has been hampered by challenges in analysis and interpretation of these information‐rich data sets. To address this issue, we have rationally combined analytical methods that report compound‐protein interactions (Inhibitor Affinity Capture/IAC; protein arrays) with technologies that monitor down‐stream cellular effects on protein signaling (Protein‐fragment Complementation Assays) and gene expression. IAC is a mass spectrometry‐based technique that discriminates tight from weaker binding proteins using a label‐free affinity binning process. Using these orthogonal approaches and pathway analysis tools, we have: 1) provided additional comprehension of mechanisms driving relevant cellular endpoints for marketed oncology drugs; 2) revealed off‐target profiles for several experimental kinase inhibitors; 3) further elucidated mechanisms of toxicity using a series of fluoroquinolone antibiotics. The multiple lines of evidence generated from this integrated technology scheme provide higher confidence decision‐making and improves the quality of compounds that are progressed towards the clinic.