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

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.