4l5b
Human dCK C4S-S74E mutant in complex with UDP and the DI-43 inhibitorHuman dCK C4S-S74E mutant in complex with UDP and the DI-43 inhibitor
Structural highlights
Publication Abstract from PubMedCombined 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 (18)F-L-1-(2'-deoxy-2'-FluoroArabinofuranosyl) Cytosine ((18)F-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 = approximately 1-12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy. Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.,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 J Med Chem. 2013 Sep 12;56(17):6696-708. doi: 10.1021/jm400457y. Epub 2013 Aug, 15. PMID:23947754[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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