title: Biochemical and transcriptional profiling to triage additional activities in a series of IGF-1R/IR inhibitors.
abstract: 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.
authors.affiliation: Applied Genomics, Bristol-Myers Squibb Research and Development, Hopewell, NJ 08534, USA. petra.rossmacdonald@bms.com
authors.forename: Petra
authors.initials: P
authors.lastname: Ross-Macdonald
authors.forename: Heshani
authors.initials: H
authors.lastname: de Silva
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.forename: Amy
authors.initials: A
authors.lastname: Truong
authors.forename: Aiqing
authors.initials: A
authors.lastname: He
authors.forename: Isaac
authors.initials: I
authors.lastname: Neuhaus
authors.forename: Charles
authors.initials: C
authors.lastname: Tilford
authors.forename: RuiRu
authors.initials: R
authors.lastname: Ji
authors.forename: Nathan
authors.initials: N
authors.lastname: Siemers
authors.forename: Ann
authors.initials: A
authors.lastname: Greer
authors.forename: Joan
authors.initials: J
authors.lastname: Carboni
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: Krista
authors.initials: K
authors.lastname: Menard
authors.forename: Frank
authors.initials: F
authors.lastname: Lee
authors.forename: Marco
authors.initials: M
authors.lastname: Dodier
authors.forename: David
authors.initials: D
authors.lastname: Frennesson
authors.forename: Anthony
authors.initials: A
authors.lastname: Sampognaro
authors.forename: Mark
authors.initials: M
authors.lastname: Saulnier
authors.forename: George
authors.initials: G
authors.lastname: Trainor
authors.forename: Dolatrai
authors.initials: D
authors.lastname: Vyas
authors.forename: Kurt
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Mark
authors.initials: M
authors.lastname: Wittman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014218:Triage
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D042863:Cyclin-Dependent Kinase 9