Skip to main content
Open Access Publications from the University of California

Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography

  • Author(s): Murphy, JM
  • Armijo, AL
  • Nomme, J
  • Lee, CH
  • Smith, QA
  • Li, Z
  • Campbell, DO
  • Liao, HI
  • Nathanson, DA
  • Austin, WR
  • Lee, JT
  • Darvish, R
  • Wei, L
  • Wang, J
  • Su, Y
  • Damoiseaux, R
  • Sadeghi, S
  • Phelps, ME
  • Herschman, HR
  • Czernin, J
  • Alexandrova, AN
  • Jung, ME
  • Lavie, A
  • Radu, CG
  • et al.

Published Web Location

Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest, and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using18F-L-1-(2′-deoxy-2′-FluoroArabinofuranosyl) Cytosine (18F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC50= ∼1-12 nM) using the18F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy. © 2013 American Chemical Society.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View