title: An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation.
abstract: Chk1 inhibition increases cell sensitivity to both chemotherapy and radiotherapy in several tumour types and is, therefore, a promising anti-cancer approach. Although several Chk1 inhibitors have been developed, their clinical progress has been hampered by low bioavailability and off-target toxicities.
  
  
  
  We characterized the radiosensitizing activity of CCT244747, the first orally bioavailable Chk1 inhibitor. We used a panel of bladder and head and neck cancer cell lines and monitored the effect of combining CCT244747 with radiation both in in vitro and in vivo models.
  
  
  
  CCT244747 sensitized cancer cell lines to radiation in vitro and resulted in a growth delay in cancer xenograft models associated with a survival benefit. Radiosensitization was elicited by abrogation of the radiation-induced G2 arrest and premature entry into mitosis.
  
  
  
  CCT244747 is a potent and specific Chk1 inhibitor that can be administered orally. It radiosensitizes tumour cell lines and represents a new therapy for clinical application in combination with radiotherapy.
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Radhika
authors.initials: R
authors.lastname: Patel
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Barker
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Joan
authors.initials: J
authors.lastname: Kyula
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: Department of Head and Neck, The Royal Marsden Hospital, United Kingdom.
authors.forename: Magnus T
authors.initials: MT
authors.lastname: Dillon
authors.affiliation: Department of Head and Neck, The Royal Marsden Hospital, United Kingdom.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schick
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Hind
authors.initials: H
authors.lastname: Hafsi
authors.affiliation: Department of Urology, The Royal Marsden Hospital, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Department of Urology, The Royal Marsden Hospital, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Khoo
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom. Electronic address: shane.zaidi@icr.ac.uk.
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D006657:Histones / Q000032:analysis; D006801:Humans; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000473:pathology / Q000532:radiotherapy*
chemical_list: C577959:3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile; D000631:Aminopyridines; C468783:H2AX protein, human; D006657:Histones; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D000071877:Checkpoint Kinase 1
keywords: Bladder cancer; Chk1 inhibition; Head and neck cancer; Radiation; Radiosensitization