开发新型脱氧胞苷激酶抑制剂并利用正电子发射断层扫描进行非侵入性体内评估。
Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.
机构信息
Department of Molecular and Medical Pharmacology, §Ahmanson Translational Imaging Division, ⊥Department of Chemistry and Biochemistry, #California NanoSystems Institute, △Department of Biological Chemistry, University of California, Los Angeles , 650 Charles E. Young Dr. S., Los Angeles, California 90095, United States.
出版信息
J Med Chem. 2013 Sep 12;56(17):6696-708. doi: 10.1021/jm400457y. Epub 2013 Aug 15.
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.
联合抑制核糖核苷酸还原酶和脱氧胞苷激酶（dCK）在多种癌细胞系中耗尽脱氧胞苷三磷酸池，导致 DNA 复制应激、细胞周期停滞和细胞凋亡。dCK 参与癌细胞增殖和存活的证据激发了我们开发小分子 dCK 抑制剂的兴趣。在对多样化化学文库进行高通量筛选后，进行了构效关系研究。正电子发射断层扫描（PET）使用（18）F-L-1-（2'-脱氧-2'-氟阿拉伯呋喃糖基）胞嘧啶（（18）F-L-FAC），一种 dCK 特异性底物，用于根据其在体内抑制 dCK 活性的能力快速对先导化合物进行排名。使用（18）F-L-FAC PET 药效动力学测定法评估细胞培养中最有效化合物的亚组（IC50=∼1-12 nM），确定了具有优异体内疗效的化合物。
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