Design, Synthesis, and Characterization of Peptide-Based Rab Geranylgeranyl Transferase Inhibitors

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• 作者：Kui-Thong Tan ; Ester Guiu-Rozas ; Robin S. Bon ; Zhong Guo ; Christine Delon ; Stefan Wetzel ; Sabine Arndt ; Kirill Alexandrov ; Herbert Waldmann ; Roger S. Goody ; Yao-Wen Wu ; Wulf Blankenfeldt
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：December 24, 2009
• 年：2009
• 卷：52
• 期：24
• 页码：8025-8037
• 全文大小：1266K
• 年卷期：v.52,no.24(December 24, 2009)
• ISSN：1520-4804

文摘

Rab geranylgeranyl transferase (RabGGTase) catalyzes the attachment of geranylgeranyl isoprenoids to Rab guanine triphosphatases, which are key regulators in vesicular transport. Because geranylgeranylation is required for proper function and overexpression of Rabs has been observed in various cancers, RabGGTase may be a target for novel therapeutics. The development of selective inhibitors is, however, difficult because two related enzymes involved in other cellular processes exist in eukaryotes and because RabGGTase recognizes protein substrates indirectly, resulting in relaxed specificity. We report the synthesis of a peptidic library based on the farnesyl transferase inhibitor pepticinnamin E. Of 469 compounds investigated, several were identified as selective for RabGGTase with low micromolar IC₅₀ values. The compounds were not generally cytotoxic and inhibited Rab isoprenylation in COS-7 cells. Crystal structure analysis revealed that selective inhibitors interact with a tunnel unique to RabGGTase, implying that this structural motif is an attractive target for improved RabGGTase inhibitors.