Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, USA.
J Med Chem. 2010 Oct 14;53(19):6867-88. doi: 10.1021/jm1001748.
A potent class of anticancer, human farnesyltransferase (hFTase) inhibitors has been identified by "piggy-backing" on potent, antimalarial inhibitors of Plasmodium falciparum farnesyltransferase (PfFTase). On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure-activity relationship (SAR) study reported herein. Our most potent inhibitor is compound 1f, which exhibited an in vitro hFTase IC(50) value of 25 nM and a whole cell H-Ras processing IC(50) value of 90 nM. Moreover, it is noteworthy that several of our inhibitors proved highly selective for hFTase (up to 333-fold) over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of inhibitor 1a co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of 1a is stabilized by a π-π stacking interaction with the Y361β residue, suggesting a structural explanation for the observed importance of this component of our inhibitors.
一种有效的抗癌药物，人法呢基转移酶（hFTase）抑制剂，是通过“搭便车”于有效的抗疟药物恶性疟原虫法呢基转移酶（PfFTase）抑制剂而被发现的。基于 4 位取代的乙二胺支架，这些抑制剂结构简单且易于衍生化，有利于广泛的构效关系（SAR）研究。我们最有效的抑制剂是化合物 1f，它在体外 hFTase IC50 值为 25 nM，全细胞 H-Ras 加工 IC50 值为 90 nM。此外，值得注意的是，我们的几种抑制剂对 hFTase 的选择性很高（高达 333 倍），而对相关的prenyltransferase 酶 geranylgeranyltransferase-I（GGTase-I）则较低。抑制剂 1a 与 FPP 共结晶的晶体结构在大鼠 FTase 的活性部位，说明了 1a 的对苯二腈部分通过与 Y361β 残基的π-π 堆积相互作用而稳定，这为我们的抑制剂中这一成分的重要性提供了结构解释。
