title: Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families.
abstract: ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.
authors.affiliation: Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
authors.forename: Junling
authors.initials: J
authors.lastname: Li
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Magoc
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: David R
authors.initials: DR
authors.lastname: Reuter
authors.forename: Paul
authors.initials: P
authors.lastname: Tapang
authors.forename: Ru-Qi
authors.initials: RQ
authors.lastname: Wei
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Pease
authors.forename: Mai H
authors.initials: MH
authors.lastname: Bui
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Robin R
authors.initials: RR
authors.lastname: Frey
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Osterling
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Olson
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Yanping
authors.initials: Y
authors.lastname: Luo
authors.forename: Michael L
authors.initials: ML
authors.lastname: Curtin
authors.forename: Cherrie K
authors.initials: CK
authors.lastname: Donawho
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
authors.forename: Chris
authors.initials: C
authors.lastname: Tse
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006657:Histones / Q000037:antagonists & inhibitors; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D010671:Phenylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D006657:Histones; D010671:Phenylurea Compounds; C577638:ilorasertib; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D019061:src-Family Kinases; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases