title: SCH 1473759, a novel Aurora inhibitor, demonstrates enhanced anti-tumor activity in combination with taxanes and KSP inhibitors.
abstract: OBJECTIVE
  Aurora kinases are required for orderly progression of cells through mitosis, and inhibition of these kinases by siRNA or small molecule inhibitors results in cell death. We previously reported the synthesis of SCH 1473759, a novel sub-nanomolar Aurora A/B inhibitor.
  
  
  METHODS
  We utilized SCH 1473759 and a panel of tumor cell lines and xenograft models to gain knowledge about optimal dosing schedule and chemotherapeutic combinations for Aurora A/B inhibitors.
  
  
  RESULTS
  SCH 1473759 was active against a large panel of tumor cell lines from different tissue origin and genetic backgrounds. Asynchronous cells required 24-h exposure to SCH 1473759 for maximal induction of >4 N DNA content and inhibition of cell growth. However, following taxane- or KSP inhibitor-induced mitotic arrest, less than 4-h exposure induced >4 N DNA content. This finding correlated with the ability of SCH 1473759 to accelerate exit from mitosis in response to taxane- and KSP inhibitor-induced arrest. We tested various dosing schedules in vivo and demonstrated SCH 1473759 dose- and schedule-dependent anti-tumor activity in four human tumor xenograft models. Further, the efficacy was enhanced in combination with taxanes and found to be most efficacious when SCH 1473759 was dosed 12-h post-taxane treatment.
  
  
  CONCLUSIONS
  SCH 1473759 demonstrated potent mechanism-based activity, and activity was shown to be enhanced in combination with taxanes and KSP inhibitors. This information may be useful for optimizing the clinical efficacy of Aurora inhibitors.
authors.affiliation: Department of Oncology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. andrea.basso@merck.com
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Basso
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gray
authors.forename: Seema
authors.initials: S
authors.lastname: Tevar
authors.forename: Suining
authors.initials: S
authors.lastname: Lee
authors.forename: Lianzhu
authors.initials: L
authors.lastname: Liang
authors.forename: Abdul
authors.initials: A
authors.lastname: Ponery
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Smith
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Monsma
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.forename: Yonglian
authors.initials: Y
authors.lastname: Zhang
authors.forename: Angela D
authors.initials: AD
authors.lastname: Kerekes
authors.forename: Sara
authors.initials: S
authors.lastname: Esposite
authors.forename: Yushi
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jayaram R
authors.initials: JR
authors.lastname: Tagat
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D007093:Imidazoles; C470243:KIF11 protein, human; D011719:Pyrazines; C568063:SCH 1473759; D043823:Taxoids; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016547:Kinesins