Development of new deoxycytidine kinase inhibitors and non-invasive in vivo evaluation using Positron Emission Tomography
Abstract:
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) using 18F-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 the 18F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.
J Med Chem. 2013 Sep 12; 56(17): 6696–6708.
Published online 2013 Aug 15. doi: 10.1021/jm400457y