Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2011 Jan;67(1):137-45. doi: 10.1007/s00280-010-1300-6. Epub 2010 Mar 13.
AZD3409 is a novel DPTI that has potent activity against both FTase and GGTase-1. The in vitro inhibition profile of AZD3409 was characterized using three different cell lines: mouse embryogenic fibroblasts, transfected with H-Ras(V12) (MEF), A549 cells (Ki4B-Ras mutation) and MCF-7 cells (no Ras mutation).
Both cytotoxicity and levels of inhibition of farnesylation and geranylgeranylation were determined in different assays in relation to the concentration of AZD3409. Results were compared with those obtained with the first-generation FTase inhibitor lonafarnib or the GGTase-1 inhibitor GGTI-2147.
The mean IC(50) for cytotoxicity of AZD3409 and lonafarnib was 510 and 15,200 nM in MEF cells, 10,600 and 2,740 nM in A549 cells and 6,170 and 9,490 nM in MCF7 cells, respectively. In these cells, the IC(50) for FTase activity of AZD3409 ranged from 3.0 to 14.2 nM and of lonafarnib from 0.26 to 31.3 nM. The inhibiting activity of AZD3409 and lonafarnib on general protein farnesylation was comparable with the specific farnesylation levels of HDJ-2. In vitro geranylgeranylation of Rap1a could be inhibited by GGTI-2147 in all three cell lines, but only in MCF-7 cells by AZD3409. These results are in agreement with the IC(50) values for GGTase-1 activity as the lowest IC(50) for AZD3409 was found in the MCF-7 cell line.
AZD3409 inhibits farnesylation to a higher extent than geranylgeranylation. Both inhibition of farnesylation and geranylgeranylation could not be correlated to the antiproliferative activity of the drug.
AZD3409 是一种新型的 DPTI，对 FTase 和 GGTase-1 均具有很强的抑制活性。使用三种不同的细胞系：转染 H-Ras(V12)的小鼠胚胎成纤维细胞（MEF）、A549 细胞（Ki4B-Ras 突变）和 MCF-7 细胞（无 Ras 突变），对 AZD3409 的体外抑制谱进行了特征描述。
在不同的测定中，根据 AZD3409 的浓度，同时测定细胞毒性和法尼基化和香叶基香叶基化的抑制水平。结果与第一代 FTase 抑制剂 lonafarnib 或 GGTase-1 抑制剂 GGTI-2147 进行了比较。
AZD3409 和 lonafarnib 在 MEF 细胞中的平均细胞毒性 IC50 分别为 510 和 15200 nM，在 A549 细胞中的分别为 10600 和 2740 nM，在 MCF7 细胞中的分别为 6170 和 9490 nM。在这些细胞中，AZD3409 的 FTase 活性 IC50 范围为 3.0 至 14.2 nM，lonafarnib 的 IC50 范围为 0.26 至 31.3 nM。AZD3409 和 lonafarnib 对普通蛋白法尼基化的抑制活性与 HDJ-2 的特异性法尼基化水平相当。在三种细胞系中，GGTI-2147 均可抑制 Rap1a 的体外香叶基香叶基化，但只有 AZD3409 可在 MCF-7 细胞中抑制。这些结果与 GGTase-1 活性的 IC50 值一致，因为 AZD3409 的最低 IC50 值是在 MCF-7 细胞系中发现的。
AZD3409 对法尼基化的抑制程度高于香叶基香叶基化。法尼基化和香叶基香叶基化的抑制均不能与药物的抗增殖活性相关联。
