Development of selective, potent RabGGTase inhibitors

Stigter, E. Anouk, Guo, Zhong, Bon, Robin S., Wu, Yao-Wen, Choidas, Axel, Wolf, Alexander, Menninger, Sascha, Waldmann, Herbert, Blankenfeldt, Wulf and Goody, Roger S. (2012) Development of selective, potent RabGGTase inhibitors. Journal of Medicinal Chemistry, 55 19: 8330-8340. doi:10.1021/jm300624s

Author Stigter, E. Anouk
Guo, Zhong
Bon, Robin S.
Wu, Yao-Wen
Choidas, Axel
Wolf, Alexander
Menninger, Sascha
Waldmann, Herbert
Blankenfeldt, Wulf
Goody, Roger S.
Title Development of selective, potent RabGGTase inhibitors
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2012-10-11
Year available 2012
Sub-type Article (original research)
DOI 10.1021/jm300624s
Open Access Status Not yet assessed
Volume 55
Issue 19
Start page 8330
End page 8340
Total pages 11
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
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 [3H]geranylgeranyl groups to Rab was used. Selective RabGGTase inhibition allows the establishment of novel drug discovery programs aimed at the development of anticancer therapeutics.
Keyword Chemistry, Medicinal
Pharmacology & Pharmacy
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 268309
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 18 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 20 times in Scopus Article | Citations
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