An orally bioavailable Chk1 inhibitor, CCT244747, sensitizes bladder and head and neck cancer cell lines to radiation

Radiother Oncol. 2017 Mar;122(3):470-475. doi: 10.1016/j.radonc.2016.12.026. Epub 2017 Jan 25.


Purpose: 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.

Materials and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Bladder cancer; Chk1 inhibition; Head and neck cancer; Radiation; Radiosensitization.

MeSH terms

  • Administration, Oral
  • Aminopyridines / pharmacology*
  • Animals
  • Cell Line, Tumor
  • Checkpoint Kinase 1 / antagonists & inhibitors*
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / radiotherapy*
  • Histones / analysis
  • Humans
  • Mice
  • Pyrimidines / pharmacology*
  • Radiation-Sensitizing Agents / pharmacology*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / radiotherapy*


  • 3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile
  • Aminopyridines
  • H2AX protein, human
  • Histones
  • Pyrimidines
  • Radiation-Sensitizing Agents
  • Checkpoint Kinase 1