Article

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.

Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA.
Journal of Medicinal Chemistry (impact factor: 4.8). 05/2010; 53(9):3454-64. DOI:10.1021/jm900232u pp.3454-64
Source: PubMed

ABSTRACT 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.

0 0
 · 
0 Bookmarks
 · 
35 Views
  • Article: Development of Selective, Potent RabGGTase Inhibitors.
    E Anouk Stigter, Zhong Guo, Robin S Bon, Yao-Wen Wu, Axel Choidas, Alexander Wolf, Sascha Menninger, Herbert Waldmann, Wulf Blankenfeldt, Roger S Goody
    [show abstract] [hide abstract]
    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 [(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.
    Journal of Medicinal Chemistry 09/2012; 55(19):8330-40. · 4.80 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

2-(3-pyridyl)-1-hydroxyethylidenebis(phosphonic acid)
 
2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid
 
3-(3-Pyridyl)-2-hydroxy-2-phosphonopropanoic acid
 
3-IPEHPC
 
4-fold
 
assays
 
biological studies
 
chiral HPLC
 
decreases bone resorption
 
inhibiting farnesyl pyrophosphate synthase
 
inhibiting Rab prenylation
 
isolated RGGT inhibition assay
 
minodronic acid 4
 
phosphonocarboxylate
 
prenylation inhibition assays
 
Rab GTPases
 
Rap 1A prenylation
 
risedronic acid
 
smaller potency difference
 
weakly inhibits Rab geranylgeranyl transferase
 

Charles E McKenna