title: Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen.
abstract: OBJECTIVE
  Aurora kinases play a key role in mitotic progression. Over-expression of Aurora kinases is found in several human cancers and correlated with histological malignancy and clinical outcomes. Therefore, Aurora kinase inhibitors should be useful in the treatment of cancers.
  
  
  METHODS
  Cell-based screening methods have an advantage over biochemical approaches because hits can be optimized to inhibit targets in the proper intracellular context. We developed a novel Aurora kinase inhibitor R763/AS703569 using an image-based phenotypic screen. The anti-proliferative effect was examined in a panel of tumor cell lines and primary cells. The efficacy was determined in a broad panel of xenograft models.
  
  
  RESULTS
  R763/AS703569 inhibits Aurora kinases, along with a limited number of other kinases including FMS-related tyrosine kinase 3 (FLT3), and has potent anti-proliferative activity against many cell types accompanying unique phenotypic changes such as enlarged cell size, endoreduplication and apoptosis. The endoreduplication cycle induced by R763/AS703569 was irreversible even after the compound was withdrawn from the culture. Oral administration of R763/AS703569 demonstrated marked inhibition of tumor growth in xenograft models of pancreatic, breast, colon, ovarian, and lung tumors and leukemia. An acute myeloid leukemia cell line MV4-11, which carries a FLT3 internal tandem duplication mutation, is particularly sensitive to R763/AS703569 in vivo.
  
  
  CONCLUSIONS
  R763/AS703569 is a potent inhibitor of Aurora kinases and exhibited significant anti-proliferative activity against a wide range of tumor cells both in vitro and in vivo. Inhibition of Aurora kinases has the potential to be a new addition to the treatment of cancers.
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.forename: Vadim
authors.initials: V
authors.lastname: Markovtsov
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Steve
authors.initials: S
authors.lastname: Wong
authors.forename: Marina
authors.initials: M
authors.lastname: Gelman
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Christian
authors.initials: C
authors.lastname: Franci
authors.forename: D  Wayne
authors.initials: D
authors.lastname: Lang
authors.forename: Erlina
authors.initials: E
authors.lastname: Pali
authors.forename: Joe
authors.initials: J
authors.lastname: Lasaga
authors.forename: Caroline
authors.initials: C
authors.lastname: Low
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhao
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.forename: Tarikere L
authors.initials: TL
authors.lastname: Gururaja
authors.forename: Weiduan
authors.initials: W
authors.lastname: Xu
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baluom
authors.forename: David
authors.initials: D
authors.lastname: Sweeny
authors.forename: David
authors.initials: D
authors.lastname: Carroll
authors.forename: Arvinder
authors.initials: A
authors.lastname: Sran
authors.forename: Sambaiah
authors.initials: S
authors.lastname: Thota
authors.forename: Manjeet
authors.initials: M
authors.lastname: Parmer
authors.forename: Angela
authors.initials: A
authors.lastname: Romane
authors.forename: George
authors.initials: G
authors.lastname: Clemens
authors.forename: Elliott
authors.initials: E
authors.lastname: Grossbard
authors.forename: Kunbin
authors.initials: K
authors.lastname: Qu
authors.forename: Yonchu
authors.initials: Y
authors.lastname: Jenkins
authors.forename: Taisei
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Vanessa
authors.initials: V
authors.lastname: Taylor
authors.forename: Sacha J
authors.initials: SJ
authors.lastname: Holland
authors.forename: Ankush
authors.initials: A
authors.lastname: Argade
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Polly
authors.initials: P
authors.lastname: Pine
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hitoshi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005434:Flow Cytometry; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D016513:Mice, SCID; D008856:Microscopy, Fluorescence / Q000379:methods*; D009636:Norbornanes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: C000592140:MSC1992371A; D009636:Norbornanes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases