title: Replicated, replicable and relevant-target engagement and pharmacological experimentation in the 21st century.
abstract: A pharmacological experiment is typically conducted to: i) test or expand a hypothesis regarding the potential role of a target in the mechanism(s) underlying a disease state using an existing drug or tool compound in normal and/or diseased tissue or animals; or ii) characterize and optimize a new chemical entity (NCE) targeted to modulate a specific disease-associated target to restore homeostasis as a potential drug candidate. Hypothesis testing necessitates an intellectually rigorous, null hypothesis approach that is distinct from a high throughput fishing expedition in search of a hypothesis. In conducting an experiment, the protocol should be transparently defined along with its powering, design, appropriate statistical analysis and consideration of the anticipated outcome (s) before it is initiated. Compound-target interactions often involve the direct study of phenotype(s) unique to the target at the cell, tissue or animal/human level. However, in vivo studies are often compromised by a lack of sufficient information on the compound pharmacokinetics necessary to ensure target engagement and also by the context-free analysis of ubiquitous cellular signaling pathways downstream from the target. The use of single tool compounds/drugs at one concentration in engineered cell lines frequently results in reductionistic data that have no physiologically relevance. This overview, focused on trends in the peer-reviewed literature, discusses the execution and reporting of experiments and the criteria recommended for the physiologically-relevant assessment of target engagement to identify viable new drug targets and facilitate the advancement of translational studies.
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Kenakin
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Bylund
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Myron L
authors.initials: ML
authors.lastname: Toews
authors.affiliation: Profectus Pharma Consulting Inc., San Jose, CA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Mullane
authors.affiliation: Department of Integrated Biology, Vertex Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Winquist
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: rivoli1635@comcast.net.
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends*; D055808:Drug Discovery / Q000379:methods* / Q000639:trends*; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000639:trends; D057166:High-Throughput Screening Assays; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000502:physiology
chemical_list: D004364:Pharmaceutical Preparations
keywords: Drug discovery; Pharmacology; Receptors; Systems biology; Target engagement