Design, synthesis, and characterization of peptide-based rab geranylgeranyl transferase inhibitors

Tan, Kui-Thong, Guiu-Rozas, Ester, Bon, Robin S., Guo, Zhong, Delon, Christine, Wetzel, Stefan, Arndt, Sabine, Alexandrov, Kirill, Waldmann, Herbert, Goody, Roger. S., Wu, Yao-Wen and Blankenfeldt, Wulf (2009) Design, synthesis, and characterization of peptide-based rab geranylgeranyl transferase inhibitors. Journal of Medicinal Chemistry, 52 24: 8025-8037. doi:10.1021/jm901117d


Author Tan, Kui-Thong
Guiu-Rozas, Ester
Bon, Robin S.
Guo, Zhong
Delon, Christine
Wetzel, Stefan
Arndt, Sabine
Alexandrov, Kirill
Waldmann, Herbert
Goody, Roger. S.
Wu, Yao-Wen
Blankenfeldt, Wulf
Title Design, synthesis, and characterization of peptide-based rab geranylgeranyl transferase inhibitors
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2009-12-01
Year available 2009
Sub-type Article (original research)
DOI 10.1021/jm901117d
Volume 52
Issue 24
Start page 8025
End page 8037
Total pages 13
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2010
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
060107 Enzymes
Abstract 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.
Keyword SOLID-PHASE SYNTHESIS
PEPTICINNAMIN-E LIBRARY
PRENYLTRANSFERASE INHIBITORS
PROTEIN FARNESYLTRANSFERASE
FLUOROMETRIC ASSAY
LIPIDATED PEPTIDES
ESCORT PROTEIN-1
NATURAL-PRODUCTS
CANCER
IDENTIFICATION
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 27 Dec 2009, 10:02:01 EST