UCLA

Background

Deoxycytidine kinase (dCK) is an essential enzyme for production of nucleotides via the salvage pathway; DI-87 is a novel dCK inhibitor in preclinical development for use in anticancer therapy. The current study utilizes PET imaging to evaluate PK-PD relationships and to determine optimal dosing of the drug.

Methods

NSG mice bearing CEM tumors had plasma and tumor PK assessed using mass spectrometry following oral administration of DI-87. dCK inhibition was assessed after a single dose of oral DI-87 followed by a [¹⁸F]CFA PET probe and PET imaging. Tumor growth inhibition was assessed by orally administering DI-87 with concurrent intraperitoneal thymidine.

Results

DI-87 had an in vitro EC₅₀ of 10.2 nM with low protein binding. Peak DI-87 concentrations were observed between 1-3 h and 3-9 h in plasma and tumor, respectively, with tumor concentrations less than one third of plasma. Full dCK inhibition, as evaluated by PET imaging, was observed as early as 3 h following 25 mg/kg dosing and was maintained for 12 h, with full recovery of enzyme activity after 36 h. When DI-87 was administered as repeated doses in combination with thymidine, full dCK inhibition was maintained at 12 h (25 mg/kg twice daily dose) and led to maximal tumor growth inhibition.

Conclusions

DI-87 is a promising new compound for use in combination therapy against tumors expressing dCK. Utilizing a [¹⁸F]CFA PET probe targeting the pathway of interest allowed for efficient and accurate identification of the optimal dose for growth inhibition.