AG2034: A novel inhibitor of glycinamide ribonucleotide formyltransferase
AG2034: A novel inhibitor of glycinamide ribonucleotide formyltransferase
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DOI：
10.1007/bf00194533
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发表时间：
1996-01-01
影响因子：
3.4
通讯作者：
Jackson, RC
中科院分区：
文献类型：
--
作者：
Boritzki, TJ;Barlett, CA;Jackson, RC
甘氨酰胺核糖核苷酸甲酰转移酶（GARFT）抑制剂4-[2-（2-氨基-4-氧代-4，6，7，8-四氢-3H-嘧啶并[5，4-b][1，4]噻嗪-6-基）-（S）-乙基]-2，5-噻吩甲酰-L-谷氨酸（AG 2034）是根据人三功能酶的GARFT结构域的X射线结构设计的。AG 2034抑制人GARFT（Ki = 28 nM），对叶酸受体具有高亲和力（Kd = 0.0042 nM），并且是大鼠肝叶酰聚谷氨酸合成酶的底物（Ki = 6.4 μ M，V-maz = 0.48 nmole/hr/mg）。对培养的L1210细胞和CCRF-CEM细胞的生长抑制IC 50分别为4 nM和2.9 nM。体外生长抑制可通过向培养基中添加次黄嘌呤或AICA（5-氨基咪唑-4-甲酰胺）逆转。还原叶酸转运受损的细胞系L1210/CI 920 [1]对AG 2034具有抗性，表明该化合物可通过利用还原叶酸载体进入细胞。AG 2034显示出对6C 3 HED、C3 HBA和B-16鼠肿瘤以及HxGC（3）、KM 20 L2、LX-1和H460人异种移植物模型的体内抗肿瘤活性，并且已被选择用于临床前开发以进行临床试验。
The glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-6][1,4]thiazin-6-yl)-(S)-ethyl]-2,5-thienoyl-L-glutamic acid (AG2034), was designed from the X-ray structure of the GARFT domain of the human tri functional enzyme. AG2034 inhibits human GARFT (K-i = 28 nM), has a high affinity for the folate receptor (K-d = 0.0042 nM), and is a substrate for rat liver folylpolyglutamate synthetase (K-m = 6.4 mu M, V-maz = 0.48 nmole/hr/mg). The IC50 for growth inhibition was 4 nM against L1210 cells and 2.9 nM for CCRF-CEM cells in culture. In vitro growth inhibition can be reversed by addition of either hypoxanthine or AICA (5-aminoimidazole-4-carboxamide) to the culture medium.A cell line with impaired transport of reduced folates, L1210/CI920 [1], was resistant to AG2034 indicating that this compound can enter cells by utilizing the reduced folate carrier. AG2034 showed in vivo antitumor activity against the 6C3HED, C3HBA, and B-16 murine tumors and in the HxGC(3), KM20L2, LX-1, and H460 human xenograft models, and has been selected for preclinical development towards clinical trials.