Biochemical and transcriptional profiling to triage additional activities in a series of IGF-1R/IR inhibitors
作者:Petra Ross-Macdonald、Heshani de Silva、Vishal Patel、Amy Truong、Aiqing He、Isaac Neuhaus、Charles Tilford、RuiRu Ji、Nathan Siemers、Ann Greer、Joan Carboni、Marco Gottardis、Krista Menard、Frank Lee、Marco Dodier、David Frennesson、Anthony Sampognaro、Mark Saulnier、George Trainor、Dolatrai Vyas、Kurt Zimmermann、Mark Wittman
DOI:10.1016/j.bmc.2011.10.090
日期:2012.3
Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series. (C) 2011 Elsevier Ltd. All rights reserved.