2. Academic Validation
  3. Development and preclinical pharmacology of a novel dCK inhibitor, DI-87

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

  • Biochem Pharmacol. 2020 Feb;172:113742. doi: 10.1016/j.bcp.2019.113742.
Soumya Poddar 1,  Edmund V Capparelli 2,  Ethan W Rosser 3,  Raymond M Gipson 4,  Liu Wei 1,  Thuc Le 1,  Michael E Jung 5,  Caius Radu 1,  Mina Nikanjam 6
Affiliations

Affiliations

  • 1 Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, United States.
  • 2 Division of Host-Microbe Systems, University of California San Diego, San Diego, CA, United States.
  • 3 Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, United States; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, United States.
  • 4 Department of Chemistry and Biochemistry, Santa Clara University, Santa Clara, CA, United States.
  • 5 Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, United States.
  • 6 Division of Hematology-Oncology, University of California San Diego, La Jolla, CA, United States. Electronic address: [email protected].
PMID: 31812677 DOI: 10.1016/j.bcp.2019.113742
Abstract

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.

Keywords

DI-87; Deoxycytidine kinase; PET scan; Pharmacodynamics; Pharmacokinetics; Preclinical.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-133141
    98.97%, dCK Inhibitor