Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
J Med Chem. 2012 Oct 11;55(19):8330-40. doi: 10.1021/jm300624s. Epub 2012 Oct 3.
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 [(3)H]geranylgeranyl groups to Rab was used. Selective RabGGTase inhibition allows the establishment of novel drug discovery programs aimed at the development of anticancer therapeutics.
Ras 家族的小 GTP 酶成员在癌症中经常发生突变。因此，已经开发出抑制剂来通过抑制这些 GTP 酶的法尼基转移酶 (FTase)、GGTase I 和 RabGGTase 的预修饰酶活性来解决这些 GTP 酶的活性问题。与 FTase 和 GGTase I 不同，只有少数 RabGGTase 抑制剂被开发出来。直到最近，已知最有效的 RabGGTase 抑制剂是一种 FTase 抑制剂，它作为一个非靶点作用于 RabGGTase。我们最近报告了我们努力调整这些抑制剂对 RabGGTase 的选择性。在这里，我们描述了一套扩展的选择性抑制剂。通过多个晶体结构的指导，详细描述了选择性 RabGGTase 抑制剂的要求。为了将体外和细胞活性联系起来，使用高通量测定系统来检测 [(3)H]法尼基基团与 Rab 的附着。选择性 RabGGTase 抑制允许建立新的药物发现计划，旨在开发抗癌治疗药物。
