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

McKenna, Charles E.; Kashemirov, B. A.; Błażewska, K. M.; Mallard-Favier, Isabelle; Stewart, Charlotte A.; Rojas, Javier; Lundy, Mark W.; Ebetino, Frank H.; Baron, Rudi; Dunford, J E; Kirsten, Marie L.; Seabra, Miguel C.; Bala, Joy Lynn F; Marma, Mong S.; Rogers, Michael J.; Coxon, Fraser P.

doi:10.1021/jm900232u

Cited by 57 publications

(54 citation statements)

References 54 publications

(96 reference statements)

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“…For Rab proteins, as prenylation is responsible for membrane delivery and it is mediated by a RabGGTase (Rab geranylgeranyltransferase) which covalently attaches two (or, in a few cases, one) geranylgeranyl moieties to cysteine residues at their C-terminus, inhibitors of RabGGTase have been used [48,49].…”

Section: How To Control Rab7 Activity?mentioning

confidence: 99%

Molecular basis of Charcot–Marie–Tooth type 2B disease

Bucci

Luca

2012

Biochemical Society Transactions

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CMT2B (Charcot-Marie-Tooth type 2B) disease is an autosomal dominant peripheral neuropathy whose onset is in the second or third decade of life, thus in adolescence or young adulthood. CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. Rab7 is a ubiquitous protein that regulates transport to late endosomes and lysosomes in the endocytic pathway. In neurons, Rab7 is important for endosomal trafficking and signalling of neurotrophins, and for retrograde axonal transport. Recent data on CMT2B-causing Rab7 mutant proteins show that these proteins exhibit altered koff rates and, as a consequence, they are mainly in the GTP-bound state and bind more strongly to Rab7 effector proteins. Notably, expression of CMT2B-causing Rab7 mutant proteins strongly inhibit neurite outgrowth in several cells lines and alter NGF (nerve growth factor) trafficking and signalling. These data indicate that Rab7 plays an essential role in neuronal cells and that CMT2B-causing Rab7 mutant proteins alter neuronal specific pathways, but do not fully explain why only peripheral neurons are affected in CMT2B. In the present paper, we discuss the current understanding of the molecular and cellular mechanisms underlying CMT2B, and we consider possible hypotheses in order to explain how alterations of Rab7 function lead to CMT2B.

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Section: How To Control Rab7 Activity?mentioning

confidence: 99%

Molecular basis of Charcot–Marie–Tooth type 2B disease

Bucci

Luca

2012

Biochemical Society Transactions

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“…15−18 Phosphonocarboxylate inhibitors led to the development of a low micromolar, specific RabGGTase inhibitor, inhibiting only the first prenylation step. 19,20 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). 21 Here we describe in detail the requirements for selective RabGGTase inhibitors, using the tetrahydrobenzodiazepine (THB) as a guiding scaffold.…”

Section: ■ Introductionmentioning

confidence: 99%

Development of Selective, Potent RabGGTase Inhibitors

et al. 2012

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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.

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“…Reported IC 50 values for PEHPC against GGTase II range from ~32 to ~600 uM. 14–16 Furthermore, formal deletion of the OH group (i.e. compound 2 ) does not greatly diminish activity against GGTase II, 11 and the enantiomers of 1 differ in activity by only ~4-fold.…”

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confidence: 99%

“…compound 2 ) does not greatly diminish activity against GGTase II, 11 and the enantiomers of 1 differ in activity by only ~4-fold. 16 In contrast the phosphono carboxylate 4 , also known as IPEHPC and viewed as an analogue of the bisphosphonate minodronate ( 5 ), 12,17 shows significantly greater potency even as the racemate, and the (+)-enantiomer 4 is ~60-fold more active than the (−)-enantiomer. 15 However, the (+)-enantiomer also shows weak inhibition of at least one other enzyme involved in isoprenoid biosynthesis, probably geranylgeranyl diphosphate synthase (GGDPS).…”

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confidence: 99%

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N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation

Zhou

Born

Allen

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.

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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

Cited by 57 publications

References 54 publications

Molecular basis of Charcot–Marie–Tooth type 2B disease

Molecular basis of Charcot–Marie–Tooth type 2B disease

Development of Selective, Potent RabGGTase Inhibitors

N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation

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