Development of Selective, Potent RabGGTase Inhibitors
Development of Selective, Potent RabGGTase Inhibitors
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DOI：
10.1021/jm300624s
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发表时间：
2012-10-11
影响因子：
7.3
通讯作者：
Goody, Roger S.
中科院分区：
文献类型：
--
作者：
Stigter, E. Anouk;Guo, Zhong;Goody, Roger S.
小GTP酶的Ras超家族成员在癌症中经常突变。因此，已经开发了抑制剂以通过抑制这些GTP酶的异戊烯化酶FT酶、GGT酶I和RabGGT酶来解决这些GTP酶的活性。与FTase和GGT酶I相反，仅开发了少数RabGGT酶抑制剂。直到最近已知的最活跃的RabGGT酶抑制剂是FTase抑制剂，其将RabGGT酶作为脱靶点。我们最近报道了我们努力调整这些抑制剂对RabGGT酶的选择性。在这里，我们描述了一组扩展的选择性抑制剂。选择性RabGGT酶抑制剂的要求进行了详细描述，指导多晶体结构。为了关联体外和细胞活性，使用高通量测定系统来检测[H-3]香叶基香叶基与Rab的连接。选择性RabGGT酶抑制允许建立旨在开发抗癌治疗剂的新药发现计划。
Members of the Ras superfamily of small GTPases are frequently mutated in cancer. Therefore, inhibitors have been developed to address the acitivity of these GTPases by inhibiting their prenylating enzymes FTase, GGTase I, and RabGGTase. In contrast to FTase and GGTase I, only a handful of RabGGTase inhibitors have been developed. The most active RabGGTase inhibitor known until recently was an FTase inhibitor which hit RabGGTase as an off-target. We recently reported our efforts to tune the selectivity of these inhibitors toward RabGGTase. Here we describe an extended set of selective inhibitors. The requirements for selective RabGGTase inhibitors are described in detail, guided by multiple crystal structures. In order to relate in vitro and cellular activity, a high-throughput assay system to detect the attachment of [H-3]geranylgeranyl groups to Rab was used. Selective RabGGTase inhibition allows the establishment of novel drug discovery programs aimed at the development of anticancer therapeutics.