4L5B

Human dCK C4S-S74E mutant in complex with UDP and the DI-43 inhibitor

4L5B の概要

• エントリーDOI: 10.2210/pdb4l5b/pdb
• 関連するPDBエントリー: 4JLK
• 分子名称: Deoxycytidine kinase, 1-[5-(4-{[(4,6-diaminopyrimidin-2-yl)sulfanyl]methyl}-5-propyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]-2-methylpropan-2-ol, URIDINE-5'-DIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: phosphoryl transfer, phosphorylation, deoxycytidine kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P27707
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67162.83

構造登録者

Nomme, J.,Lavie, A. (登録日: 2013-06-10, 公開日: 2013-09-18, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.94 Å)