DeMartino Jessica K, Hwang Inkyu, Xu Lan, Wilson Ian A, Boger Dale L
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
J Med Chem. 2006 May 18;49(10):2998-3002. doi: 10.1021/jm0601147.
Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors. Herein we report the discovery of a potent, nonpolyglutamatable, and selective inhibitor of GAR Tfase. Compound 12, which possesses a tetrazole in place of the gamma-carboxylic acid in the l-glutamate subunit of the potent GAR Tfase inhibitor 1, was active in cellular-based functional assays exhibiting purine-sensitive cytotoxic activity (IC(50) = 40 nM, CCRF-CEM) and was selective for inhibition of rhGAR Tfase (K(i) = 130 nM). Notably, 12 was only 2.5-fold less potent than 1 in cellular assays and 4-fold less potent against rhGAR Tfase. Like 1, this functional activity of 12 in the cell-based assay benefits from and requires transport into the cell by the reduced folate carrier but, unlike 1, is independent of folyl polyglutamate synthase (FPGS) expression levels and polyglutamation.
甘氨酰胺核苷酸转甲酰酶（GAR Tfase）催化从头嘌呤生物合成途径中两个需要叶酸辅因子的甲酰基转移步骤中的第一步。在此，我们报告了一种强效、不可聚谷氨酸化且具有选择性的GAR Tfase抑制剂的发现。化合物12在强效GAR Tfase抑制剂1的L-谷氨酸亚基中用四唑取代了γ-羧酸，在基于细胞的功能测定中具有活性，表现出对嘌呤敏感的细胞毒性活性（IC(50)=40 nM，CCRF-CEM），并且对rhGAR Tfase的抑制具有选择性（K(i)=130 nM）。值得注意的是，在细胞测定中，12的效力仅比1低2.5倍，对rhGAR Tfase的效力低4倍。与1一样，12在基于细胞的测定中的这种功能活性得益于并需要通过还原型叶酸载体转运到细胞中，但与1不同的是，它与叶酰聚谷氨酸合成酶（FPGS）的表达水平和聚谷氨酸化无关。
