title: Adaptation of the plasma inhibitory activity assay to detect Aurora, ABL and FLT3 kinase inhibition by AT9283 in pediatric leukemia.
abstract: Non-invasive assessment of biomarker modulation is important for evaluating targeted therapeutics, particularly in pediatrics. The plasma inhibitory activity (PIA) assay is used clinically to assess FLT3 inhibition ex vivo and guide dosing. AT9283 is a novel Aurora kinase inhibitor with secondary activity against FLT3 and ABL. We adapted the PIA assay to simultaneously detect inhibition of Aurora and FLT3 in AML, and Aurora and ABL in CML by AT9283. Furthermore, we optimized the assay for children, where limited blood volumes are available for pharmacodynamic studies. Simultaneously detecting multiple kinase inhibition may identify important mechanisms of action for novel anti-leukemic drugs.
authors.affiliation: Section of Pediatric Oncology, The Institute of Cancer Research, Sutton, UK.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Podesta
authors.forename: Richard
authors.initials: R
authors.lastname: Sugar
authors.forename: Matt
authors.initials: M
authors.lastname: Squires
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
authors.forename: Andrew D J
authors.initials: AD
authors.lastname: Pearson
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Moore
mesh_terms: D017668:Age of Onset; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D064127:Aurora Kinases; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001774:Blood Chemical Analysis / Q000379:methods / Q000592:standards; D002138:Calibration; D045744:Cell Line, Tumor; D002648:Child; D004353:Drug Evaluation, Preclinical; D057075:Enzyme Assays / Q000379:methods / Q000592:standards; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C535237:1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D016374:Oncogene Proteins v-abl; D047428:Protein Kinase Inhibitors; D014508:Urea; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases