Development of Selective RabGGTase Inhibitors and Crystal Structure of a RabGGTase–Inhibitor Complex

Guo, Zhong; Wu, Yao‐Wen; Tan, Kui‐Thong; Bon, Robin S.; Guiu-Rozas, Ester; Delon, Christine; Nguyen, Uyen; Wetzel, Stefan; Arndt, Sabine; Goody, Roger S.; Blankenfeldt, Wulf; Alexandrov, Kirill; Waldmann, Herbert

doi:10.1002/anie.200705795

Cited by 17 publications

(28 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The data demonstrate that (+)- 3 -E1 is the most potent selective PC inhibitor of RGGT yet to be identified. Other selective inhibitors of RGGT are similar in potency toward this enzyme in vitro (IC 50 values 2.1−2.8 μM) but less effective in whole cell prenylation assays (inhibition of Rab prenylation at 20−50 μM) . Although the compound BMS-1 is a more potent inhibitor than (+)- 3 -E1 in enzyme assays, this compound is also a potent inhibitor of FTase …”

Section: Biological Activity Of 1 and 3 Stereoisomersmentioning

confidence: 99%

“…Rab proteins such as Rab11 and Rab25 may contribute to the aggressiveness and progression of various cancers, including those that frequently metastasize to bone. , RGGT is overexpressed in a subset of human tumors, and there is evidence that the anticancer effects of some compounds designed as inhibitors of FPPS might involve suppression of prenylation mediated by RGGT, stimulating interest in the design of specific inhibitors for this enzyme . PC analogues of N-BP drugs exhibit antitumor properties in vitro, both by inhibiting cell invasion and reducing cell viability, and 1 has exhibited direct antitumor activity in an animal model …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis, Chiral High Performance Liquid Chromatographic Resolution and Enantiospecific Activity of a Potent New Geranylgeranyl Transferase Inhibitor, 2-Hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic Acid

et al. 2010

View full text Add to dashboard Cite

3-(3-Pyridyl)-2-hydroxy-2-phosphonopropanoic acid (3-PEHPC, 1) is a phosphonocarboxylate (PC) analogue of 2-(3-pyridyl)-1-hydroxyethylidenebis(phosphonic acid) (risedronic acid, 2), an osteoporosis drug that decreases bone resorption by inhibiting farnesyl pyrophosphate synthase (FPPS) in osteoclasts, preventing protein prenylation. 1 has lower bone affinity than 2 and weakly inhibits Rab geranylgeranyl transferase (RGGT), selectively preventing prenylation of Rab GTPases. We report here the synthesis and biological studies of 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC, 3), the PC analogue of minodronic acid 4. Like 1, 3 selectively inhibited Rab11 vs. Rap 1A prenylation in J774 cells, and decreased cell viability, but was 33-60x more active in these assays. After resolving 3 by chiral HPLC (>98% ee), we found that (+)-3-E1 was much more potent than (-)-3-E2 in an isolated RGGT inhibition assay, approximately 17x more potent (LED 3 microM) than (-)-3-E2 in inhibiting Rab prenylation in J774 cells and >26x more active in the cell viability assay. The enantiomers of 1 exhibited a 4-fold or smaller potency difference in the RGGT and prenylation inhibition assays.

show abstract

Section: Biological Activity Of 1 and 3 Stereoisomersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis, Chiral High Performance Liquid Chromatographic Resolution and Enantiospecific Activity of a Potent New Geranylgeranyl Transferase Inhibitor, 2-Hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic Acid

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Other Rab proteins have elevated expression in various human cancers . However, only a few specific RGGT inhibitors (Figure ) are available, and they typically have low affinities. ,− …”

Section: Protein Prenylationmentioning

confidence: 99%

Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies

et al. 2018

View full text Add to dashboard Cite

Protein lipidation, including cysteine prenylation, N-terminal glycine myristoylation, cysteine palmitoylation, and serine and lysine fatty acylation, occurs in many proteins in eukaryotic cells and regulates numerous biological pathways, such as membrane trafficking, protein secretion, signal transduction, and apoptosis. We provide a comprehensive review of protein lipidation, including descriptions of proteins known to be modified and the functions of the modifications, the enzymes that control them, and the tools and technologies developed to study them. We also highlight key questions about protein lipidation that remain to be answered, the challenges associated with answering such questions, and possible solutions to overcome these challenges.

show abstract

“…Compounds that scored high for RabGGTase and low for FTase were expected to represent selective RabGGTase inhibitors that correctly approach the TAG tunnel. Several groups in addition to the furanaldehyde (16) and furannitrile (17) could be identified. Heteroaromatic groups such as pyridine point toward the TAG tunnel without distorting the general binding character.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…Rab GTPases and their interacting proteins are involved in cancer, genetic diseases, and pathogen uptake mechanisms. , However, only a few RabGGTase inhibitors have been developed. − Phosphonocarboxylate inhibitors led to the development of a low micromolar, specific RabGGTase inhibitor, inhibiting only the first prenylation step. , Recently, we reported a potent highly selective RabGGTase inhibitor, which inhibits cellular Rab prenylation and proliferation of several cancer cell lines without displaying general cytotoxicity to human peripheral blood cells (PMBCs) …”

Section: Introductionmentioning

confidence: 99%

Development of Selective, Potent RabGGTase Inhibitors

et al. 2012

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Development of Selective RabGGTase Inhibitors and Crystal Structure of a RabGGTase–Inhibitor Complex

Cited by 17 publications

References 20 publications

Synthesis, Chiral High Performance Liquid Chromatographic Resolution and Enantiospecific Activity of a Potent New Geranylgeranyl Transferase Inhibitor, 2-Hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic Acid

Synthesis, Chiral High Performance Liquid Chromatographic Resolution and Enantiospecific Activity of a Potent New Geranylgeranyl Transferase Inhibitor, 2-Hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic Acid

Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies

Development of Selective, Potent RabGGTase Inhibitors

Contact Info

Product

Resources

About