4JLK

Human dCK C4S-S74E mutant in complex with UDP and the F2.2.1 inhibitoR (2-[({2-[3-(2-FLUOROETHOXY)-4-METHOXYPHENYL]-5-METHYL-1,3-THIAZOL-4-YL}METHYL)SULFANYL]PYRIMIDINE-4,6-DIAMINE)

Summary for 4JLK

• Entry DOI: 10.2210/pdb4jlk/pdb
• Related: 4JLM 4JLN 4jlj
• Descriptor: Deoxycytidine kinase, URIDINE-5'-DIPHOSPHATE, 2-[({2-[3-(2-fluoroethoxy)-4-methoxyphenyl]-5-methyl-1,3-thiazol-4-yl}methyl)sulfanyl]pyrimidine-4,6-diamine, ... (4 entities in total)
• Functional Keywords: phosphoryl transfer, phosphorylation, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P27707
• Total number of polymer chains: 2
• Total formula weight: 67897.62

Authors

Nomme, J.,Lavie, A. (deposition date: 2013-03-12, release date: 2013-09-18, Last modification date: 2024-02-28)

Primary citation

Murphy, J.M.,Armijo, A.L.,Nomme, J.,Lee, C.H.,Smith, Q.A.,Li, Z.,Campbell, D.O.,Liao, H.I.,Nathanson, D.A.,Austin, W.R.,Lee, J.T.,Darvish, R.,Wei, L.,Wang, J.,Su, Y.,Damoiseaux, R.,Sadeghi, S.,Phelps, M.E.,Herschman, H.R.,Czernin, J.,Alexandrova, A.N.,Jung, M.E.,Lavie, A.,Radu, C.G.
Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.
J.Med.Chem., 56:6696-6708, 2013

PubMed 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 (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 = ∼1-12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.

PubMed: 23947754
DOI: 10.1021/jm400457y

Experimental method

X-RAY DIFFRACTION (1.89 Å)