Development and preclinical pharmacology of a novel dCK inhibitor, DI-87.

摘要: Abstract Background Deoxycytidine kinase (dCK) is an essential enzyme for production of nucleotides via the salvage pathway; DI-87 a novel dCK inhibitor in preclinical development use anticancer therapy. The current study utilizes PET imaging to evaluate PK-PD relationships and determine optimal dosing drug. Methods NSG mice bearing CEM tumors had plasma tumor PK assessed using mass spectrometry following oral administration DI-87. inhibition was after single dose followed by [18F]CFA probe imaging. Tumor growth orally administering with concurrent intraperitoneal thymidine. Results vitro EC50 10.2 nM low protein binding. Peak concentrations were observed between 1–3 h 3–9 h tumor, respectively, less than one third plasma. Full inhibition, as evaluated imaging, early 3 h 25 mg/kg maintained 12 h, full recovery activity 36 h. When administered repeated doses combination thymidine, at 12 h (25 mg/kg twice daily dose) led maximal inhibition. Conclusions promising new compound therapy against expressing dCK. Utilizing targeting pathway interest allowed efficient accurate identification