title: Minimum significant ratio of selectivity ratios (MSRSR) and confidence in ratio of selectivity ratios (CRSR): quantitative measures for selectivity ratios obtained by screening assays.
abstract: Development of inhibitor compounds selective against undesirable targets is critical in drug discovery. Selectivity ratios for candidate compounds are evaluated by dividing potencies from two assays assessing the off-target and target. Because all potency measurements have underlying uncertainty, understanding error propagation is essential to interpreting selectivity data. Assay noise introduces ambiguity in the statistical significance of selectivity ratios, particularly at low replicate numbers when compounds are often prioritized for subsequent testing. The ability to differentiate potency results for any pair of compounds in one assay is evaluated using a metric called minimum significant ratio (MSR). Potency results of one compound tested in a pair of assays can be differentiated by the minimum significant selectivity ratio (MSSR). To differentiate selectivity ratios for any pair of compounds, we extend this concept by proposing two new parameters called the minimum significant ratio of selectivity ratios (MSRSR) and confidence in ratio of selectivity ratios (CRSR). Importantly, these tools can be used after a single selectivity measurement. We describe these methods and illustrate their usefulness using structure-activity relationship data from a Janus kinase inhibitor project, in which these tools informed a cogent retesting strategy and enabled rapid and objective decision making.
authors.affiliation: Abbott Laboratories, Worcester, MA 01605, USA. eric.goedken@abbott.com
authors.forename: Eric R
authors.initials: ER
authors.lastname: Goedken
authors.forename: Viswanath
authors.initials: V
authors.lastname: Devanarayan
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Harris
authors.forename: Lori A
authors.initials: LA
authors.lastname: Dowding
authors.forename: James P
authors.initials: JP
authors.lastname: Jakway
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Voss
authors.forename: Neil
authors.initials: N
authors.lastname: Wishart
authors.forename: David C
authors.initials: DC
authors.lastname: Jordan
authors.forename: Robert V
authors.initials: RV
authors.lastname: Talanian
mesh_terms: D002468:Cell Physiological Phenomena; D003627:Data Interpretation, Statistical; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000032:analysis*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D053612:Janus Kinases