|
Inhibitory activity against the human recombinant FPPSase (Farnesyl diphosphate) enzyme
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents.
Year : 2002
Volume : 45
Issue : 11
First Page : 2185
Last Page : 2196
Authors : Szabo CM, Matsumura Y, Fukura S, Martin MB, Sanders JM, Sengupta S, Cieslak JA, Loftus TC, Lea CR, Lee HJ, Koohang A, Coates RM, Sagami H, Oldfield E.
Abstract : We report the inhibition of a human recombinant geranylgeranyl diphosphate synthase (GGPPSase) by 23 bisphosphonates and six azaprenyl diphosphates. The IC50 values range from 140 nM to 690 microM. None of the nitrogen-containing bisphosphonates that inhibit farnesyl diphosphate synthase were effective in inhibiting the GGPPSase enzyme. Using three-dimensional quantitative structure-activity relationship/comparative molecular field analysis (CoMFA) methods, we find a good correlation between experimental and predicted activity: R2 = 0.938, R(cv)2 = 0.900, R(bs)2 = 0.938, and F-test = 86.8. To test the predictive utility of the CoMFA approach, we used three training sets of 25 compounds each to generate models to predict three test sets of three compounds. The rms pIC50 error for the nine predictions was 0.39. We also investigated the pharmacophore of these GGPPSase inhibitors using the Catalyst method. The results demonstrated that Catalyst predicted the pIC50 values for the nine test set compounds with an rms error of 0.28 (R2 between experimental and predicted activity of 0.948).
|
Inhibitory activity against Leishmania major Farnesyl diphosphate synthase
|
Leishmania major
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Effects of bisphosphonates on the growth of Entamoeba histolytica and Plasmodium species in vitro and in vivo.
Year : 2004
Volume : 47
Issue : 1
First Page : 175
Last Page : 187
Authors : Ghosh S, Chan JM, Lea CR, Meints GA, Lewis JC, Tovian ZS, Flessner RM, Loftus TC, Bruchhaus I, Kendrick H, Croft SL, Kemp RG, Kobayashi S, Nozaki T, Oldfield E.
Abstract : The effects of a series of 102 bisphosphonates on the inhibition of growth of Entamoeba histolytica and Plasmodium falciparum in vitro have been determined, and selected compounds were further investigated for their in vivo activity. Forty-seven compounds tested were active (IC(50) < 200 microM) versus E. histolytica growth in vitro. The most active compounds (IC(50) approximately 4-9 microM) were nitrogen-containing bisphosphonates with relatively large aromatic side chains. Simple n-alkyl-1-hydroxy-1,1-bisphosphonates, known inhibitors of the enzyme farnesylpyrophosphate (FPP) synthase, were also active, with optimal activity being found with C9-C10 side chains. However, numerous other nitrogen-containing bisphosphonates known to be potent FPP synthase inhibitors, such as risedronate or pamidronate, had little or no activity. Several pyridine-derived bisphosphonates were quite active (IC(50) approximately 10-20 microM), and this activity was shown to correlate with the basicity of the aromatic group, with activity decreasing with increasing pK(a) values. The activities of all compounds were tested versus a human nasopharyngeal carcinoma (KB) cell line to enable an estimate of the therapeutic index (TI). Five bisphosphonates were selected and then screened for their ability to delay the development of amebic liver abscess formation in an E. histolytica infected hamster model. Two compounds were found to decrease liver abscess formation at 10 mg/kg ip with little or no effect on normal liver mass. With P. falciparum, 35 compounds had IC(50) values <200 microM in an in vitro assay. The most active compounds were also simple n-alkyl-1-hydroxy-1,1-bisphosphonates, having IC(50) values around 1 microM. Five compounds were again selected for in vivo investigation in a Plasmodium berghei ANKA BALB/c mouse suppressive test. The most active compound, a C9 n-alkyl side chain containing bisphosphonate, caused an 80% reduction in parasitemia with no overt toxicity. Taken together, these results show that bisphosphonates appear to be useful lead compounds for the development of novel antiamebic and antimalarial drugs.
|
Inhibitory activity against farnesyl Pyrophosphate Synthase was determined
|
Leishmania major
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-D QSAR investigations of the inhibition of Leishmania major farnesyl pyrophosphate synthase by bisphosphonates.
Year : 2003
Volume : 46
Issue : 24
First Page : 5171
Last Page : 5183
Authors : Sanders JM, Gómez AO, Mao J, Meints GA, Van Brussel EM, Burzynska A, Kafarski P, González-Pacanowska D, Oldfield E.
Abstract : We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC(50) values) ranging from approximately 100 nM to approximately 80 microM (corresponding to K(i) values as low as 10 nM). The most active compounds were found to be zoledronate (whose single-crystal X-ray structure is reported), pyridinyl-ethane-1-hydroxy-1,1-bisphosphonates or picolyl aminomethylene bisphosphonates. However, N-alicyclic aminomethylene bisphosphonates, such as incadronate (N-cycloheptyl aminomethylene bisphosphonate), as well as aliphatic aminomethylene bisphosphonates containing short (n = 4, 5) alkyl chains, were also active, with IC(50) values in the 200-1700 nM range (corresponding to K(i) values of approximately 20-170 nM). Bisphosphonates containing longer or multiple (N,N-) alkyl substitutions were inactive, as were aromatic species lacking an o- or m-nitrogen atom in the ring, or possessing multiple halogen substitutions or a p-amino group. To put these observations on a more quantitative structural basis, we used three-dimensional quantitative structure-activity relationship techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), to investigate which structural features correlated with high activity. Training set results (N = 62 compounds) yielded good correlations with each technique (R(2) = 0.87 and 0.88, respectively), and were further validated by using a training/test set approach. Test set results (N = 24 compounds) indicated that IC(50) values could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods, respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate side chain and a hydrophobic feature contributed significantly to activity. Overall, these results are of general interest since they represent the first detailed quantitative structure-activity relationship study of the inhibition of an expressed farnesyl pyrophosphate synthase enzyme by bisphosphonate inhibitors and that the activity of these inhibitors can be predicted within about a factor of 3 by using 3D-QSAR techniques.
|
Binding affinity towards farnesyl Pyrophosphate Synthase using [14C]- isopentenyl pyrophosphate as radioligand
|
Leishmania major
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-D QSAR investigations of the inhibition of Leishmania major farnesyl pyrophosphate synthase by bisphosphonates.
Year : 2003
Volume : 46
Issue : 24
First Page : 5171
Last Page : 5183
Authors : Sanders JM, Gómez AO, Mao J, Meints GA, Van Brussel EM, Burzynska A, Kafarski P, González-Pacanowska D, Oldfield E.
Abstract : We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC(50) values) ranging from approximately 100 nM to approximately 80 microM (corresponding to K(i) values as low as 10 nM). The most active compounds were found to be zoledronate (whose single-crystal X-ray structure is reported), pyridinyl-ethane-1-hydroxy-1,1-bisphosphonates or picolyl aminomethylene bisphosphonates. However, N-alicyclic aminomethylene bisphosphonates, such as incadronate (N-cycloheptyl aminomethylene bisphosphonate), as well as aliphatic aminomethylene bisphosphonates containing short (n = 4, 5) alkyl chains, were also active, with IC(50) values in the 200-1700 nM range (corresponding to K(i) values of approximately 20-170 nM). Bisphosphonates containing longer or multiple (N,N-) alkyl substitutions were inactive, as were aromatic species lacking an o- or m-nitrogen atom in the ring, or possessing multiple halogen substitutions or a p-amino group. To put these observations on a more quantitative structural basis, we used three-dimensional quantitative structure-activity relationship techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), to investigate which structural features correlated with high activity. Training set results (N = 62 compounds) yielded good correlations with each technique (R(2) = 0.87 and 0.88, respectively), and were further validated by using a training/test set approach. Test set results (N = 24 compounds) indicated that IC(50) values could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods, respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate side chain and a hydrophobic feature contributed significantly to activity. Overall, these results are of general interest since they represent the first detailed quantitative structure-activity relationship study of the inhibition of an expressed farnesyl pyrophosphate synthase enzyme by bisphosphonate inhibitors and that the activity of these inhibitors can be predicted within about a factor of 3 by using 3D-QSAR techniques.
|
Inhibitory activity against farnesyl Pyrophosphate Synthase expressed as #NAME? (M)
|
Leishmania major
|
169.82
nM
|
|
Journal : J. Med. Chem.
Title : 3-D QSAR investigations of the inhibition of Leishmania major farnesyl pyrophosphate synthase by bisphosphonates.
Year : 2003
Volume : 46
Issue : 24
First Page : 5171
Last Page : 5183
Authors : Sanders JM, Gómez AO, Mao J, Meints GA, Van Brussel EM, Burzynska A, Kafarski P, González-Pacanowska D, Oldfield E.
Abstract : We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC(50) values) ranging from approximately 100 nM to approximately 80 microM (corresponding to K(i) values as low as 10 nM). The most active compounds were found to be zoledronate (whose single-crystal X-ray structure is reported), pyridinyl-ethane-1-hydroxy-1,1-bisphosphonates or picolyl aminomethylene bisphosphonates. However, N-alicyclic aminomethylene bisphosphonates, such as incadronate (N-cycloheptyl aminomethylene bisphosphonate), as well as aliphatic aminomethylene bisphosphonates containing short (n = 4, 5) alkyl chains, were also active, with IC(50) values in the 200-1700 nM range (corresponding to K(i) values of approximately 20-170 nM). Bisphosphonates containing longer or multiple (N,N-) alkyl substitutions were inactive, as were aromatic species lacking an o- or m-nitrogen atom in the ring, or possessing multiple halogen substitutions or a p-amino group. To put these observations on a more quantitative structural basis, we used three-dimensional quantitative structure-activity relationship techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), to investigate which structural features correlated with high activity. Training set results (N = 62 compounds) yielded good correlations with each technique (R(2) = 0.87 and 0.88, respectively), and were further validated by using a training/test set approach. Test set results (N = 24 compounds) indicated that IC(50) values could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods, respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate side chain and a hydrophobic feature contributed significantly to activity. Overall, these results are of general interest since they represent the first detailed quantitative structure-activity relationship study of the inhibition of an expressed farnesyl pyrophosphate synthase enzyme by bisphosphonate inhibitors and that the activity of these inhibitors can be predicted within about a factor of 3 by using 3D-QSAR techniques.
|
In vitro rescue of growth inhibition of Trypanosoma uM of compound
|
Trypanosoma brucei rhodesiense
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
Year : 2002
Volume : 45
Issue : 14
First Page : 2904
Last Page : 2914
Authors : Martin MB, Sanders JM, Kendrick H, de Luca-Fradley K, Lewis JC, Grimley JS, Van Brussel EM, Olsen JR, Meints GA, Burzynska A, Kafarski P, Croft SL, Oldfield E.
Abstract : We report the results of a comparative molecular field analysis (CoMFA) investigation of the growth inhibition of the bloodstream form of Trypanosoma brucei rhodesiense trypomastigotes by bisphosphonates. A quantitative three-dimensional structure-activity relationship CoMFA model for a set of 26 bisphosphonates having a range of activity spanning approximately 3 orders of magnitude (minimum IC(50) = 220 nM; maximum IC(50) = 102 microM) yielded an R(2) value of 0.87 with a cross-validated R(2) value of 0.79. The predictive utility of this approach was tested for three sets of three compounds: the average pIC(50) error was 0.23. For the nitrogen-containing bisphosphonates, in general, the activity was aromatic- >> aliphatic-containing side chains. The activity of aromatic species lacking an alkyl ring substitution decreased from ortho to meta to para substitution; halogen substitutions also reduced activity. For the aliphatic bisphosphonates, the IC(50) values decreased nearly monotonically with increasing chain length (down to IC(50) = 2.0 microM for the n-C(11) alkyl side chain species). We also show, using a "rescue" experiment, that the molecular target of the nitrogen-containing bisphosphonate, risedronate, in T. b. rhodesiense is the enzyme farnesyl pyrophosphate synthase. In addition, we report the LD(50) values of bisphosphonates in a mammalian cell general toxicity screen and present a comparison between the therapeutic indices and the IC(50) values in the T. b. rhodesiense growth inhibition assay. Several bisphosphonates were found to have large therapeutic indices (> or =200:1) as well as low IC(50) values, suggesting their further investigation as antiparasitic agents against T. b. rhodesiense.
|
In vitro rescue of growth inhibition of Trypanosoma uM of compound
|
Trypanosoma brucei rhodesiense
|
19.3
%
|
|
Journal : J. Med. Chem.
Title : Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
Year : 2002
Volume : 45
Issue : 14
First Page : 2904
Last Page : 2914
Authors : Martin MB, Sanders JM, Kendrick H, de Luca-Fradley K, Lewis JC, Grimley JS, Van Brussel EM, Olsen JR, Meints GA, Burzynska A, Kafarski P, Croft SL, Oldfield E.
Abstract : We report the results of a comparative molecular field analysis (CoMFA) investigation of the growth inhibition of the bloodstream form of Trypanosoma brucei rhodesiense trypomastigotes by bisphosphonates. A quantitative three-dimensional structure-activity relationship CoMFA model for a set of 26 bisphosphonates having a range of activity spanning approximately 3 orders of magnitude (minimum IC(50) = 220 nM; maximum IC(50) = 102 microM) yielded an R(2) value of 0.87 with a cross-validated R(2) value of 0.79. The predictive utility of this approach was tested for three sets of three compounds: the average pIC(50) error was 0.23. For the nitrogen-containing bisphosphonates, in general, the activity was aromatic- >> aliphatic-containing side chains. The activity of aromatic species lacking an alkyl ring substitution decreased from ortho to meta to para substitution; halogen substitutions also reduced activity. For the aliphatic bisphosphonates, the IC(50) values decreased nearly monotonically with increasing chain length (down to IC(50) = 2.0 microM for the n-C(11) alkyl side chain species). We also show, using a "rescue" experiment, that the molecular target of the nitrogen-containing bisphosphonate, risedronate, in T. b. rhodesiense is the enzyme farnesyl pyrophosphate synthase. In addition, we report the LD(50) values of bisphosphonates in a mammalian cell general toxicity screen and present a comparison between the therapeutic indices and the IC(50) values in the T. b. rhodesiense growth inhibition assay. Several bisphosphonates were found to have large therapeutic indices (> or =200:1) as well as low IC(50) values, suggesting their further investigation as antiparasitic agents against T. b. rhodesiense.
|
In vitro rescue of growth inhibition of Trypanosoma uM of compound
|
Trypanosoma brucei rhodesiense
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
Year : 2002
Volume : 45
Issue : 14
First Page : 2904
Last Page : 2914
Authors : Martin MB, Sanders JM, Kendrick H, de Luca-Fradley K, Lewis JC, Grimley JS, Van Brussel EM, Olsen JR, Meints GA, Burzynska A, Kafarski P, Croft SL, Oldfield E.
Abstract : We report the results of a comparative molecular field analysis (CoMFA) investigation of the growth inhibition of the bloodstream form of Trypanosoma brucei rhodesiense trypomastigotes by bisphosphonates. A quantitative three-dimensional structure-activity relationship CoMFA model for a set of 26 bisphosphonates having a range of activity spanning approximately 3 orders of magnitude (minimum IC(50) = 220 nM; maximum IC(50) = 102 microM) yielded an R(2) value of 0.87 with a cross-validated R(2) value of 0.79. The predictive utility of this approach was tested for three sets of three compounds: the average pIC(50) error was 0.23. For the nitrogen-containing bisphosphonates, in general, the activity was aromatic- >> aliphatic-containing side chains. The activity of aromatic species lacking an alkyl ring substitution decreased from ortho to meta to para substitution; halogen substitutions also reduced activity. For the aliphatic bisphosphonates, the IC(50) values decreased nearly monotonically with increasing chain length (down to IC(50) = 2.0 microM for the n-C(11) alkyl side chain species). We also show, using a "rescue" experiment, that the molecular target of the nitrogen-containing bisphosphonate, risedronate, in T. b. rhodesiense is the enzyme farnesyl pyrophosphate synthase. In addition, we report the LD(50) values of bisphosphonates in a mammalian cell general toxicity screen and present a comparison between the therapeutic indices and the IC(50) values in the T. b. rhodesiense growth inhibition assay. Several bisphosphonates were found to have large therapeutic indices (> or =200:1) as well as low IC(50) values, suggesting their further investigation as antiparasitic agents against T. b. rhodesiense.
|
In vitro rescue of growth inhibition of Trypanosoma uM of compound
|
Trypanosoma brucei rhodesiense
|
23.49
%
|
|
Journal : J. Med. Chem.
Title : Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
Year : 2002
Volume : 45
Issue : 14
First Page : 2904
Last Page : 2914
Authors : Martin MB, Sanders JM, Kendrick H, de Luca-Fradley K, Lewis JC, Grimley JS, Van Brussel EM, Olsen JR, Meints GA, Burzynska A, Kafarski P, Croft SL, Oldfield E.
Abstract : We report the results of a comparative molecular field analysis (CoMFA) investigation of the growth inhibition of the bloodstream form of Trypanosoma brucei rhodesiense trypomastigotes by bisphosphonates. A quantitative three-dimensional structure-activity relationship CoMFA model for a set of 26 bisphosphonates having a range of activity spanning approximately 3 orders of magnitude (minimum IC(50) = 220 nM; maximum IC(50) = 102 microM) yielded an R(2) value of 0.87 with a cross-validated R(2) value of 0.79. The predictive utility of this approach was tested for three sets of three compounds: the average pIC(50) error was 0.23. For the nitrogen-containing bisphosphonates, in general, the activity was aromatic- >> aliphatic-containing side chains. The activity of aromatic species lacking an alkyl ring substitution decreased from ortho to meta to para substitution; halogen substitutions also reduced activity. For the aliphatic bisphosphonates, the IC(50) values decreased nearly monotonically with increasing chain length (down to IC(50) = 2.0 microM for the n-C(11) alkyl side chain species). We also show, using a "rescue" experiment, that the molecular target of the nitrogen-containing bisphosphonate, risedronate, in T. b. rhodesiense is the enzyme farnesyl pyrophosphate synthase. In addition, we report the LD(50) values of bisphosphonates in a mammalian cell general toxicity screen and present a comparison between the therapeutic indices and the IC(50) values in the T. b. rhodesiense growth inhibition assay. Several bisphosphonates were found to have large therapeutic indices (> or =200:1) as well as low IC(50) values, suggesting their further investigation as antiparasitic agents against T. b. rhodesiense.
|
In vitro rescue of growth inhibition of Trypanosoma uM of compound
|
Trypanosoma brucei rhodesiense
|
86.49
%
|
|
Journal : J. Med. Chem.
Title : Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
Year : 2002
Volume : 45
Issue : 14
First Page : 2904
Last Page : 2914
Authors : Martin MB, Sanders JM, Kendrick H, de Luca-Fradley K, Lewis JC, Grimley JS, Van Brussel EM, Olsen JR, Meints GA, Burzynska A, Kafarski P, Croft SL, Oldfield E.
Abstract : We report the results of a comparative molecular field analysis (CoMFA) investigation of the growth inhibition of the bloodstream form of Trypanosoma brucei rhodesiense trypomastigotes by bisphosphonates. A quantitative three-dimensional structure-activity relationship CoMFA model for a set of 26 bisphosphonates having a range of activity spanning approximately 3 orders of magnitude (minimum IC(50) = 220 nM; maximum IC(50) = 102 microM) yielded an R(2) value of 0.87 with a cross-validated R(2) value of 0.79. The predictive utility of this approach was tested for three sets of three compounds: the average pIC(50) error was 0.23. For the nitrogen-containing bisphosphonates, in general, the activity was aromatic- >> aliphatic-containing side chains. The activity of aromatic species lacking an alkyl ring substitution decreased from ortho to meta to para substitution; halogen substitutions also reduced activity. For the aliphatic bisphosphonates, the IC(50) values decreased nearly monotonically with increasing chain length (down to IC(50) = 2.0 microM for the n-C(11) alkyl side chain species). We also show, using a "rescue" experiment, that the molecular target of the nitrogen-containing bisphosphonate, risedronate, in T. b. rhodesiense is the enzyme farnesyl pyrophosphate synthase. In addition, we report the LD(50) values of bisphosphonates in a mammalian cell general toxicity screen and present a comparison between the therapeutic indices and the IC(50) values in the T. b. rhodesiense growth inhibition assay. Several bisphosphonates were found to have large therapeutic indices (> or =200:1) as well as low IC(50) values, suggesting their further investigation as antiparasitic agents against T. b. rhodesiense.
|
In vitro rescue of growth inhibition of Trypanosoma uM of compound
|
Trypanosoma brucei rhodesiense
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
Year : 2002
Volume : 45
Issue : 14
First Page : 2904
Last Page : 2914
Authors : Martin MB, Sanders JM, Kendrick H, de Luca-Fradley K, Lewis JC, Grimley JS, Van Brussel EM, Olsen JR, Meints GA, Burzynska A, Kafarski P, Croft SL, Oldfield E.
Abstract : We report the results of a comparative molecular field analysis (CoMFA) investigation of the growth inhibition of the bloodstream form of Trypanosoma brucei rhodesiense trypomastigotes by bisphosphonates. A quantitative three-dimensional structure-activity relationship CoMFA model for a set of 26 bisphosphonates having a range of activity spanning approximately 3 orders of magnitude (minimum IC(50) = 220 nM; maximum IC(50) = 102 microM) yielded an R(2) value of 0.87 with a cross-validated R(2) value of 0.79. The predictive utility of this approach was tested for three sets of three compounds: the average pIC(50) error was 0.23. For the nitrogen-containing bisphosphonates, in general, the activity was aromatic- >> aliphatic-containing side chains. The activity of aromatic species lacking an alkyl ring substitution decreased from ortho to meta to para substitution; halogen substitutions also reduced activity. For the aliphatic bisphosphonates, the IC(50) values decreased nearly monotonically with increasing chain length (down to IC(50) = 2.0 microM for the n-C(11) alkyl side chain species). We also show, using a "rescue" experiment, that the molecular target of the nitrogen-containing bisphosphonate, risedronate, in T. b. rhodesiense is the enzyme farnesyl pyrophosphate synthase. In addition, we report the LD(50) values of bisphosphonates in a mammalian cell general toxicity screen and present a comparison between the therapeutic indices and the IC(50) values in the T. b. rhodesiense growth inhibition assay. Several bisphosphonates were found to have large therapeutic indices (> or =200:1) as well as low IC(50) values, suggesting their further investigation as antiparasitic agents against T. b. rhodesiense.
|
Inhibition of Toxoplasma gondii tachyzoites in human foreskin fibroblast monolayer(DMEM with 10%fetal calf serum)
|
Toxoplasma gondii
|
490.0
nM
|
|
Journal : J. Med. Chem.
Title : Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy.
Year : 2001
Volume : 44
Issue : 6
First Page : 909
Last Page : 916
Authors : Martin MB, Grimley JS, Lewis JC, Heath HT, Bailey BN, Kendrick H, Yardley V, Caldera A, Lira R, Urbina JA, Moreno SN, Docampo R, Croft SL, Oldfield E.
Abstract : We have investigated the effects in vitro of a series of bisphosphonates on the proliferation of Trypanosoma cruzi, Trypanosoma brucei rhodesiense, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum. The results show that nitrogen-containing bisphosphonates of the type used in bone resorption therapy have significant activity against parasites, with the aromatic species having in some cases nanomolar or low-micromolar IC(50) activity values against parasite replication (e.g. o-risedronate, IC(50) = 220 nM for T. brucei rhodesiense; risedronate, IC(50) = 490 nM for T. gondii). In T. cruzi, the nitrogen-containing bisphosphonate risedronate is shown to inhibit sterol biosynthesis at a pre-squalene level, most likely by inhibiting farnesylpyrophosphate synthase. Bisphosphonates therefore appear to have potential in treating parasitic protozoan diseases.
|
Effect on inhibition on proliferation of Trypanosoma cruzi Amastigotes in vero cells at a conc of 150 uM
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy.
Year : 2001
Volume : 44
Issue : 6
First Page : 909
Last Page : 916
Authors : Martin MB, Grimley JS, Lewis JC, Heath HT, Bailey BN, Kendrick H, Yardley V, Caldera A, Lira R, Urbina JA, Moreno SN, Docampo R, Croft SL, Oldfield E.
Abstract : We have investigated the effects in vitro of a series of bisphosphonates on the proliferation of Trypanosoma cruzi, Trypanosoma brucei rhodesiense, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum. The results show that nitrogen-containing bisphosphonates of the type used in bone resorption therapy have significant activity against parasites, with the aromatic species having in some cases nanomolar or low-micromolar IC(50) activity values against parasite replication (e.g. o-risedronate, IC(50) = 220 nM for T. brucei rhodesiense; risedronate, IC(50) = 490 nM for T. gondii). In T. cruzi, the nitrogen-containing bisphosphonate risedronate is shown to inhibit sterol biosynthesis at a pre-squalene level, most likely by inhibiting farnesylpyrophosphate synthase. Bisphosphonates therefore appear to have potential in treating parasitic protozoan diseases.
|
Binding affinity towards Farnesyl diphosphate synthase from leishmania major
|
Leishmania major
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption.
Year : 2005
Volume : 48
Issue : 8
First Page : 2957
Last Page : 2963
Authors : Sanders JM, Song Y, Chan JM, Zhang Y, Jennings S, Kosztowski T, Odeh S, Flessner R, Schwerdtfeger C, Kotsikorou E, Meints GA, Gómez AO, González-Pacanowska D, Raker AM, Wang H, van Beek ER, Papapoulos SE, Morita CT, Oldfield E.
Abstract : We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.
|
In vitro inhibitory concentration against bone resorption in 17 day old fetal mouse metatarsals
|
Mus musculus
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption.
Year : 2005
Volume : 48
Issue : 8
First Page : 2957
Last Page : 2963
Authors : Sanders JM, Song Y, Chan JM, Zhang Y, Jennings S, Kosztowski T, Odeh S, Flessner R, Schwerdtfeger C, Kotsikorou E, Meints GA, Gómez AO, González-Pacanowska D, Raker AM, Wang H, van Beek ER, Papapoulos SE, Morita CT, Oldfield E.
Abstract : We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.
|
Inhibitory activity against FPPS in Leishmania major
|
Leishmania major
|
170.0
nM
|
|
Inhibitory activity against FPPS in Leishmania major
|
Leishmania major
|
169.82
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of Trypanosoma cruzi hexokinase by bisphosphonates.
Year : 2006
Volume : 49
Issue : 1
First Page : 215
Last Page : 223
Authors : Hudock MP, Sanz-Rodríguez CE, Song Y, Chan JM, Zhang Y, Odeh S, Kosztowski T, Leon-Rossell A, Concepción JL, Yardley V, Croft SL, Urbina JA, Oldfield E.
Abstract : Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei). The T. cruzi enzyme is unusual since, unlike the human enzyme, it is inhibited by inorganic diphosphate (PPi). Here, we show that non-hydrolyzable analogues of PPi, bisphosphonates, are potent inhibitors of T. cruzi hexokinase (TcHK). We determined the activity of 42 bisphosphonates against TcHK, and the IC(50) values were used to construct pharmacophore and comparative molecular similarity indices analysis (CoMSIA) models for enzyme inhibition. Both models revealed the importance of electrostatic, hydrophobic, and steric interactions, and the IC(50) values for 17 active compounds were predicted with an average error of 2.4x by using the CoMSIA models. The compound most active against T. cruzi hexokinase was found to have a 2.2 microM IC(50) versus the clinically relevant intracellular amastigote form of T. cruzi, but only a approximately 1-2 mM IC(50) versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi.
|
Inhibition of human recombinant FPPS expressed in Escherichia coli BL21
|
Homo sapiens
|
452.9
nM
|
|
Inhibition of human recombinant FPPS expressed in Escherichia coli BL21
|
Homo sapiens
|
82.2
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase.
Year : 2008
Volume : 51
Issue : 7
First Page : 2187
Last Page : 2195
Authors : Dunford JE, Kwaasi AA, Rogers MJ, Barnett BL, Ebetino FH, Russell RG, Oppermann U, Kavanagh KL.
Abstract : The nitrogen-containing bisphosphonates (N-BPs) are the main drugs currently used to treat diseases characterized by excessive bone resorption. The major molecular target of N-BPs is farnesylpyrophosphate synthase. N-BPs inhibit the enzyme by a mechanism that involves time dependent isomerization of the enzyme. We investigated features of N-BPs that confer maximal slow and tight-binding by quantifying the initial and final K(i)s and calculating the isomerization constant K(isom) for many N-BPs. Disruption of the phosphonate-carbon-phosphonate backbone resulted in loss of potency and reduced K(isom). The lack of a hydroxyl group on the geminal carbon also reduced K(isom). The position of the nitrogen in the side chain was crucial to both K(i) and K(isom). A correlation of K(isom) and also final K(i) with previously published in vivo potency reveals that the isomerization constant ( R = -0.77, p < 0.0001) and the final inhibition of FPPS by N-BPs ( R = 0.74, p < 0.0001) are closely linked to antiresorptive efficacy.
|
Inhibition of human recombinant FPPS expressed in Escherichia coli BL21 after 10 mins
|
Homo sapiens
|
5.7
nM
|
|
Inhibition of human recombinant FPPS expressed in Escherichia coli BL21 after 10 mins
|
Homo sapiens
|
0.36
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase.
Year : 2008
Volume : 51
Issue : 7
First Page : 2187
Last Page : 2195
Authors : Dunford JE, Kwaasi AA, Rogers MJ, Barnett BL, Ebetino FH, Russell RG, Oppermann U, Kavanagh KL.
Abstract : The nitrogen-containing bisphosphonates (N-BPs) are the main drugs currently used to treat diseases characterized by excessive bone resorption. The major molecular target of N-BPs is farnesylpyrophosphate synthase. N-BPs inhibit the enzyme by a mechanism that involves time dependent isomerization of the enzyme. We investigated features of N-BPs that confer maximal slow and tight-binding by quantifying the initial and final K(i)s and calculating the isomerization constant K(isom) for many N-BPs. Disruption of the phosphonate-carbon-phosphonate backbone resulted in loss of potency and reduced K(isom). The lack of a hydroxyl group on the geminal carbon also reduced K(isom). The position of the nitrogen in the side chain was crucial to both K(i) and K(isom). A correlation of K(isom) and also final K(i) with previously published in vivo potency reveals that the isomerization constant ( R = -0.77, p < 0.0001) and the final inhibition of FPPS by N-BPs ( R = 0.74, p < 0.0001) are closely linked to antiresorptive efficacy.
|
Inhibition of Sulfolobus solfataricus HPPS
|
Sulfolobus solfataricus
|
90.0
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases.
Year : 2007
Volume : 104
Issue : 24
First Page : 10022
Last Page : 10027
Authors : Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH.
Abstract : Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.
|
Inhibition of Escherichia coli OPPS
|
Escherichia coli
|
38.0
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases.
Year : 2007
Volume : 104
Issue : 24
First Page : 10022
Last Page : 10027
Authors : Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH.
Abstract : Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.
|
Inhibition of human FPPS
|
Homo sapiens
|
5.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Farnesyl pyrophosphate synthase enantiospecificity with a chiral risedronate analog, [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501): Synthetic, structural, and modeling studies.
Year : 2008
Volume : 18
Issue : 9
First Page : 2878
Last Page : 2882
Authors : Deprèle S, Kashemirov BA, Hogan JM, Ebetino FH, Barnett BL, Evdokimov A, McKenna CE.
Abstract : The complex formed from crystallization of human farnesyl pyrophosphate synthase (hFPPS) from a solution of racemic [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501, 8), a chiral analog of the anti-osteoporotic drug risedronate, contained the R enantiomer in the enzyme active site. This enantiospecificity was assessed by computer modeling of inhibitor-active site interactions using Autodock 3, which was also evaluated for predictive ability in calculations of the known configurations of risedronate, zoledronate, and minodronate complexed in the active site of hFPPS. In comparison with these structures, the 8 complex exhibited certain differences, including the presence of only one Mg(2+), which could contribute to its 100-fold higher IC(50). An improved synthesis of 8 is described, which decreases the number of steps from 12 to 8 and increases the overall yield by 17-fold.
|
Inhibition of farnesyl diphosphate synthase at 2 nM
|
None
|
57.0
%
|
|
Journal : J. Med. Chem.
Title : Determination of the microscopic equilibrium dissociation constants for risedronate and its analogues reveals two distinct roles for the nitrogen atom in nitrogen-containing bisphosphonate drugs.
Year : 2008
Volume : 51
Issue : 14
First Page : 4170
Last Page : 4178
Authors : Hounslow AM, Carran J, Brown RJ, Rejman D, Blackburn GM, Watts DJ.
Abstract : Microscopic equilibrium dissociation constants, k as, were determined for four nitrogen-containing bisphosphonates (N-BP): risedronate and its analogues 2-(2-aminophenyl)-1-hydroxyethylidene-1,1-bisphosphonate, NE 11807, and NE 97220. The proportion of each and of analogues 2-(3'-( N-ethyl)pyridinium)-ethylidenebisphosphonate and 2-(3-piperinidyl)-1-hydroxyethylidene-1,1-bisphosphonate, having a positively charged nitrogen and three negative charges on the bisphosphonate group ("carbocation analogue") at pH 7.5, was calculated. When set in order of increasing potency at inhibiting farnesyl diphosphate (FDP) synthase (their intracellular target), the N-BPs are also ranked in order of decreasing mole fraction of carbocation analogue. However, only a weak correlation exists between potency for inhibiting FDP synthase and potency for inhibiting Dictyostelium discoideum growth. It is concluded that, although high potency for inhibiting FDP synthase is favored when the nitrogen atom in a N-BP is uncharged, N-BPs having a positively charged nitrogen can still be potent inhibitors of Dictyostelium growth owing to favorable interaction with a second, unidentified target.
|
Antiinflammatory activity in delayed type hypersensitivity rat model assessed as inhibition of granuloma wet weight at 100 mg/kg, sc
|
Rattus norvegicus
|
48.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, properties, and perspectives of gem-diphosphono substituted-thiazoles.
Year : 2008
Volume : 43
Issue : 5
First Page : 1015
Last Page : 1024
Authors : Abdou WM, Ganoub NA, Geronikaki A, Sabry E.
Abstract : A series of substituted arylidene thiazoles were allowed to react with Wittig-Horner (WH) reagent, tetraethyl methyl-1,1-bisphosphonate, to produce via Michael addition reaction the corresponding heteroarylmethylenebisphosphonates (BPs) in different yields according to the experimental conditions. Acid hydrolysis of the new BPs was undertaken to obtain the corresponding bisphosphonic acids. Prediction and the in vivo activity of the products in the rat adjuvant model are also discussed in terms of structure-activity relationships (SAR).
|
Antiinflammatory activity in delayed type hypersensitivity rat model assessed as inhibition of granuloma dry weight at 100 mg/kg, sc
|
Rattus norvegicus
|
44.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, properties, and perspectives of gem-diphosphono substituted-thiazoles.
Year : 2008
Volume : 43
Issue : 5
First Page : 1015
Last Page : 1024
Authors : Abdou WM, Ganoub NA, Geronikaki A, Sabry E.
Abstract : A series of substituted arylidene thiazoles were allowed to react with Wittig-Horner (WH) reagent, tetraethyl methyl-1,1-bisphosphonate, to produce via Michael addition reaction the corresponding heteroarylmethylenebisphosphonates (BPs) in different yields according to the experimental conditions. Acid hydrolysis of the new BPs was undertaken to obtain the corresponding bisphosphonic acids. Prediction and the in vivo activity of the products in the rat adjuvant model are also discussed in terms of structure-activity relationships (SAR).
|
Inhibition of Plasmodium vivax FPPS expressed in Escherichia coli BL21 by spectrophotometric assay
|
Plasmodium vivax
|
590.0
nM
|
|
Inhibition of Plasmodium vivax FPPS expressed in Escherichia coli BL21 by spectrophotometric assay
|
Plasmodium vivax
|
630.96
nM
|
|
Journal : J. Med. Chem.
Title : Bisphosphonate inhibition of a Plasmodium farnesyl diphosphate synthase and a general method for predicting cell-based activity from enzyme data.
Year : 2008
Volume : 51
Issue : 24
First Page : 7827
Last Page : 7833
Authors : Mukkamala D, No JH, Cass LM, Chang TK, Oldfield E.
Abstract : We screened 26 bisphosphonates against a farnesyl diphosphate synthase from Plasmodium vivax, finding a poor correlation between enzyme and cell growth inhibition (R(2) = 0.06). To better predict cell activity data, we then used a combinatorial descriptor search in which pIC(50)(cell) = a pIC(50)(enzyme) + bB + cC + d, where B and C are descriptors (such as SlogP), and a-d are coefficients. R(2) increased from 0.01 to 0.74 (for a leave-two-out test set of 26 predictions). The method was then further validated using data for nine other systems, including bacterial, viral, and mammalian cell systems. On average, experimental/predicted cell pIC(50) correlations increased from R(2) = 0.28 (for an enzyme-only test set) to 0.70 (for enzyme plus two descriptor test set predictions), while predictions based on scrambled cell activity had no predictive value (R(2) = 0.13). These results are of interest since they represent a general way to predict cell from enzyme inhibition data, with in three cases, R(2) values increasing from approximately 0.02 to 0.72.
|
Inhibition of N-terminal His-tagged human FPPS expressed in Escherichia coli
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase.
Year : 2010
Volume : 20
Issue : 19
First Page : 5781
Last Page : 5786
Authors : De Schutter JW, Zaretsky S, Welbourn S, Pause A, Tsantrizos YS.
Abstract : A structure-based approach was pursued in designing novel bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase (hFPPS). Preliminary SAR and structural evidence for the simultaneous binding of these inhibitors into the isopentenyl pyrophosphate (IPP) and the geranyl pyrophosphate (GPP) substrate sub-pockets of the enzyme are presented.
|
Inhibition of Trypanosoma cruzi FPPS after 30 mins using [14C]IPP by scintillation counting
|
Trypanosoma cruzi
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase.
Year : 2011
Volume : 19
Issue : 7
First Page : 2211
Last Page : 2217
Authors : Rosso VS, Szajnman SH, Malayil L, Galizzi M, Moreno SN, Docampo R, Rodriguez JB.
Abstract : The effect of long-chain 2-alkylaminoethyl-1,1-bisphosphonates against proliferation of the clinically more relevant form of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas' disease), and against tachyzoites of Toxoplasma gondii was investigated. Particularly, compound 26 proved to be an extremely potent inhibitor against the intracellular form of T. cruzi, exhibiting IC(50) values at the nanomolar range. This cellular activity was associated with a strong inhibition of the enzymatic activity of T. cruzi farnesyl diphosphate synthase (TcFPPS), which constitutes a valid target for Chagas' disease chemotherapy. Compound 26 was an effective agent against T. cruzi (amastigotes) exhibiting an IC(50) value of 0.67 μM, while this compound showed an IC(50) value of 0.81 μM against the target enzyme TcFPPS. This drug was less effective against the enzymatic activity of T. cruzi solanesyl diphosphate synthase TcSPPS showing an IC(50) value of 3.2 μM. Interestingly, compound 26 was also very effective against T. gondii (tachyzoites) exhibiting IC(50) values of 6.23 μM. This cellular activity was also related to the inhibition of the enzymatic activity towards the target enzyme TgFPPS (IC(50)=0.093 μM) As bisphosphonate-containing compounds are FDA-approved drugs for the treatment of bone resorption disorders, their potential low toxicity makes them good candidates to control different tropical diseases.
|
Inhibition of Toxoplasma gondii FPPS after 30 mins using [14C]IPP by scintillation counting
|
Toxoplasma gondii
|
74.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase.
Year : 2011
Volume : 19
Issue : 7
First Page : 2211
Last Page : 2217
Authors : Rosso VS, Szajnman SH, Malayil L, Galizzi M, Moreno SN, Docampo R, Rodriguez JB.
Abstract : The effect of long-chain 2-alkylaminoethyl-1,1-bisphosphonates against proliferation of the clinically more relevant form of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas' disease), and against tachyzoites of Toxoplasma gondii was investigated. Particularly, compound 26 proved to be an extremely potent inhibitor against the intracellular form of T. cruzi, exhibiting IC(50) values at the nanomolar range. This cellular activity was associated with a strong inhibition of the enzymatic activity of T. cruzi farnesyl diphosphate synthase (TcFPPS), which constitutes a valid target for Chagas' disease chemotherapy. Compound 26 was an effective agent against T. cruzi (amastigotes) exhibiting an IC(50) value of 0.67 μM, while this compound showed an IC(50) value of 0.81 μM against the target enzyme TcFPPS. This drug was less effective against the enzymatic activity of T. cruzi solanesyl diphosphate synthase TcSPPS showing an IC(50) value of 3.2 μM. Interestingly, compound 26 was also very effective against T. gondii (tachyzoites) exhibiting IC(50) values of 6.23 μM. This cellular activity was also related to the inhibition of the enzymatic activity towards the target enzyme TgFPPS (IC(50)=0.093 μM) As bisphosphonate-containing compounds are FDA-approved drugs for the treatment of bone resorption disorders, their potential low toxicity makes them good candidates to control different tropical diseases.
|
Inhibition of human recombinant N-terminal-His6 tagged FPPS expressed in Escherichia coli BL21 using [14C]IPP and GPP as substrate incubated for 10 mins prior to substrate addition measured after 10 mins by scintillation counting
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells.
Year : 2012
Volume : 55
Issue : 7
First Page : 3201
Last Page : 3215
Authors : Lin YS, Park J, De Schutter JW, Huang XF, Berghuis AM, Sebag M, Tsantrizos YS.
Abstract : Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the (364)KRRK(367) tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.
|
Inhibition of human recombinant N-terminal-His6 tagged FPPS expressed in Escherichia coli BL21 using [3H]IPP and GPP as substrate at 1 uM incubated for 10 mins prior to substrate addition measured after 20 mins by liquid scintillation counting
|
Homo sapiens
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells.
Year : 2012
Volume : 55
Issue : 7
First Page : 3201
Last Page : 3215
Authors : Lin YS, Park J, De Schutter JW, Huang XF, Berghuis AM, Sebag M, Tsantrizos YS.
Abstract : Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the (364)KRRK(367) tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.
|
Inhibition of human recombinant N-terminal-His6 tagged FPPS expressed in Escherichia coli BL21 using [3H]IPP and GPP as substrate measured after 20 mins by liquid scintillation counting
|
Homo sapiens
|
860.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells.
Year : 2012
Volume : 55
Issue : 7
First Page : 3201
Last Page : 3215
Authors : Lin YS, Park J, De Schutter JW, Huang XF, Berghuis AM, Sebag M, Tsantrizos YS.
Abstract : Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the (364)KRRK(367) tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.
|
Inhibition of human His6-tagged recombinant FPPS expressed in Escherichia coli BL21(DE3) using GPP and [3H]IPP as substrate incubated for 5 mins prior to substrate addition measured after 20 mins by liquid scintillation counting
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design of potent bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase via targeted interactions with the active site 'capping' phenyls.
Year : 2012
Volume : 20
Issue : 18
First Page : 5583
Last Page : 5591
Authors : De Schutter JW, Shaw J, Lin YS, Tsantrizos YS.
Abstract : Nitrogen-containing bisphosphonates (N-BPs) are potent active site inhibitors of the human farnesyl pyrophosphate synthase (hFPPS) and valuable human therapeutics for the treatment of bone-related malignancies. N-BPs are also useful in combination chemotherapy for patients with breast, prostate and multiple myeloma cancers. A structure-based approach was employed in order to design inhibitors that exhibit higher lipophilicity and better occupancy for the GPP sub-pocket of hFPPS than the current therapeutic drugs. These novel analogs were designed to bind deeper into the GPP sub-pocket by displacing the side chains of the 'capping' residue Phe 113 and engaging in favorable π-interactions with the side chain of Phe112.
|
Inhibition of human N-terminal His6-tagged recombinant human GGPS expressed in Escherichia coli BL21(DE3) using FPP and [14C]IPP as substrate at 10 uM by scintillation counting
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design of potent bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase via targeted interactions with the active site 'capping' phenyls.
Year : 2012
Volume : 20
Issue : 18
First Page : 5583
Last Page : 5591
Authors : De Schutter JW, Shaw J, Lin YS, Tsantrizos YS.
Abstract : Nitrogen-containing bisphosphonates (N-BPs) are potent active site inhibitors of the human farnesyl pyrophosphate synthase (hFPPS) and valuable human therapeutics for the treatment of bone-related malignancies. N-BPs are also useful in combination chemotherapy for patients with breast, prostate and multiple myeloma cancers. A structure-based approach was employed in order to design inhibitors that exhibit higher lipophilicity and better occupancy for the GPP sub-pocket of hFPPS than the current therapeutic drugs. These novel analogs were designed to bind deeper into the GPP sub-pocket by displacing the side chains of the 'capping' residue Phe 113 and engaging in favorable π-interactions with the side chain of Phe112.
|
Inhibition of recombinant human FPPS expressed in Escherichia coli by scintillation counting
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Remarkable potential of the α-aminophosphonate/phosphinate structural motif in medicinal chemistry.
Year : 2011
Volume : 54
Issue : 17
First Page : 5955
Last Page : 5980
Authors : Mucha A, Kafarski P, Berlicki Ł.
|
Inhibition of Toxoplasma gondii farnesyl diphosphate synthase assessed as incorporation of [4-14C]IPP measured at 37 degC
|
Toxoplasma gondii
|
74.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents.
Year : 2013
Volume : 60
First Page : 431
Last Page : 440
Authors : Recher M, Barboza AP, Li ZH, Galizzi M, Ferrer-Casal M, Szajnman SH, Docampo R, Moreno SN, Rodriguez JB.
Abstract : As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these sulfur-containing bisphosphonates were potent inhibitors against the intracellular form of T. cruzi, the clinically more relevant replicative form of this parasite, and tachyzoites of T. gondii targeting T. cruzi or T. gondii farnesyl diphosphate synthases (FPPSs), which constitute valid targets for the chemotherapy of these parasitic diseases. Interestingly, long chain length sulfur-containing bisphosphonates emerged as relevant antiparasitic agents. Taking compounds 37, 38, and 39 as representative members of this class of drugs, they exhibited ED(50) values of 15.8 μM, 12.8 μM, and 22.4 μM, respectively, against amastigotes of T. cruzi. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) having IC(50) values of 6.4 μM, 1.7 μM, and 0.097 μM, respectively. In addition, these compounds were potent anti-Toxoplasma agents. They had ED(50) values of 2.6 μM, 1.2 μM, and 1.8 μM, respectively, against T. gondii tachyzoites, while they exhibited a very potent inhibitory action against the target enzyme (TgFPPS) showing IC(50) values of 0.024 μM, 0.025 μM, and 0.021 μM, respectively. Bisphosphonates bearing a sulfoxide unit at C-3 were also potent anti-Toxoplasma agents, particularly those bearing long aliphatic chains such as 43-45, which were also potent antiproliferative drugs against tachyzoites of T. gondii. These compounds inhibited the enzymatic activity of the target enzyme (TgFPPS) at the very low nanomolar range. These bisphosphonic acids have very good prospective not only as lead drugs but also as potential chemotherapeutic agents.
|
Inhibition of Trypanosoma cruzi farnesyl diphosphate synthase assessed as incorporation of [4-14C]IPP measured at 37 degC
|
Trypanosoma cruzi
|
27.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents.
Year : 2013
Volume : 60
First Page : 431
Last Page : 440
Authors : Recher M, Barboza AP, Li ZH, Galizzi M, Ferrer-Casal M, Szajnman SH, Docampo R, Moreno SN, Rodriguez JB.
Abstract : As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these sulfur-containing bisphosphonates were potent inhibitors against the intracellular form of T. cruzi, the clinically more relevant replicative form of this parasite, and tachyzoites of T. gondii targeting T. cruzi or T. gondii farnesyl diphosphate synthases (FPPSs), which constitute valid targets for the chemotherapy of these parasitic diseases. Interestingly, long chain length sulfur-containing bisphosphonates emerged as relevant antiparasitic agents. Taking compounds 37, 38, and 39 as representative members of this class of drugs, they exhibited ED(50) values of 15.8 μM, 12.8 μM, and 22.4 μM, respectively, against amastigotes of T. cruzi. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) having IC(50) values of 6.4 μM, 1.7 μM, and 0.097 μM, respectively. In addition, these compounds were potent anti-Toxoplasma agents. They had ED(50) values of 2.6 μM, 1.2 μM, and 1.8 μM, respectively, against T. gondii tachyzoites, while they exhibited a very potent inhibitory action against the target enzyme (TgFPPS) showing IC(50) values of 0.024 μM, 0.025 μM, and 0.021 μM, respectively. Bisphosphonates bearing a sulfoxide unit at C-3 were also potent anti-Toxoplasma agents, particularly those bearing long aliphatic chains such as 43-45, which were also potent antiproliferative drugs against tachyzoites of T. gondii. These compounds inhibited the enzymatic activity of the target enzyme (TgFPPS) at the very low nanomolar range. These bisphosphonic acids have very good prospective not only as lead drugs but also as potential chemotherapeutic agents.
|
Inhibition of human recombinant FPPS using GPP/[3H]IPP as substrate incubated for 10 mins prior to substrate addition measured after 8 mins by scintillation counting analysis
|
Homo sapiens
|
5.2
nM
|
|
Journal : J. Med. Chem.
Title : Thienopyrimidine bisphosphonate (ThPBP) inhibitors of the human farnesyl pyrophosphate synthase: optimization and characterization of the mode of inhibition.
Year : 2013
Volume : 56
Issue : 20
First Page : 7939
Last Page : 7950
Authors : Leung CY, Park J, De Schutter JW, Sebag M, Berghuis AM, Tsantrizos YS.
Abstract : Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.
|
Inhibition of human recombinant FPPS using GPP/[3H]IPP as substrate incubated for 10 mins prior to substrate addition by scintillation counting analysis
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Thienopyrimidine bisphosphonate (ThPBP) inhibitors of the human farnesyl pyrophosphate synthase: optimization and characterization of the mode of inhibition.
Year : 2013
Volume : 56
Issue : 20
First Page : 7939
Last Page : 7950
Authors : Leung CY, Park J, De Schutter JW, Sebag M, Berghuis AM, Tsantrizos YS.
Abstract : Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.
|
Inhibition of Toxoplasma gondii recombinant FPPS expressed in Escherichia coli using [4-14C]IPP/DMAPP/GPP as substrate after 30 mins by scintillation counting analysis
|
Toxoplasma gondii
|
74.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : New insights into molecular recognition of 1,1-bisphosphonic acids by farnesyl diphosphate synthase.
Year : 2014
Volume : 22
Issue : 1
First Page : 398
Last Page : 405
Authors : Ferrer-Casal M, Li C, Galizzi M, Stortz CA, Szajnman SH, Docampo R, Moreno SN, Rodriguez JB.
Abstract : As part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bisphosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED₅₀ value of 4.7 μM against tachyzoites of T. gondii and an IC₅₀ of 0.051 μM against TgFPPS.
|
Inhibition of Trypanosoma cruzi recombinant FPPS assessed as incorporation of [4-14C]IPP with DMAPP into [4-14C]FPP after 30 mins by scintillation counting analysis
|
Trypanosoma cruzi
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : New insights into molecular recognition of 1,1-bisphosphonic acids by farnesyl diphosphate synthase.
Year : 2014
Volume : 22
Issue : 1
First Page : 398
Last Page : 405
Authors : Ferrer-Casal M, Li C, Galizzi M, Stortz CA, Szajnman SH, Docampo R, Moreno SN, Rodriguez JB.
Abstract : As part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bisphosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED₅₀ value of 4.7 μM against tachyzoites of T. gondii and an IC₅₀ of 0.051 μM against TgFPPS.
|
Allosteric inhibition of human recombinant FPPS using GPP and [3H]IPP as substrate incubated with enzyme for 10 mins prior to substrate addition by liquid scintillation counting analysis
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Multistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: implications to drug discovery for neurodegenerative diseases.
Year : 2014
Volume : 57
Issue : 13
First Page : 5764
Last Page : 5776
Authors : De Schutter JW, Park J, Leung CY, Gormley P, Lin YS, Hu Z, Berghuis AM, Poirier J, Tsantrizos YS.
Abstract : Human farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer from poor "drug-like" properties and are mainly effective in treating skeletal diseases. Recent investigations have implicated hFPPS in various nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are strongly implicated in AD progression. The development of nonbisphosphonate inhibitors can provide molecular tools for validating hFPPS as a therapeutic target for tauopathy-associated neurodegeneration. A multistage screening protocol led to the identification of a new monophosphonate chemotype that bind in an allosteric pocket of hFPPS. Optimization of these compounds could lead to human therapeutics that block tau metabolism and arrest the progression of neurodegeneration.
|
Inhibition of human FPPS
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase.
Year : 2015
Volume : 25
Issue : 5
First Page : 1117
Last Page : 1123
Authors : Gritzalis D, Park J, Chiu W, Cho H, Lin YS, De Schutter JW, Lacbay CM, Zielinski M, Berghuis AM, Tsantrizos YS.
Abstract : In order to explore the interactions of bisphosphonate ligands with the active site and an allosteric pocket of the human farnesyl pyrophosphate synthase (hFPPS), substituted indole and azabenzimidazole bisphosphonates were designed as chameleon ligands. NMR and crystallographic studies revealed that these compounds can occupy both sub-pockets of the active site cavity, as well as the allosteric pocket of hFPPS in the presence of the enzyme's Mg(2+) ion cofactor. These results are consistent with the previously proposed hypothesis that the allosteric pocket of hFPPS, located near the active site, plays a feed-back regulatory role for this enzyme.
|
Inhibition of FDPS (unknown origin)
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation.
Year : 2015
Volume : 25
Issue : 11
First Page : 2331
Last Page : 2334
Authors : Zhou X, Born EJ, Allen C, Holstein SA, Wiemer DF.
Abstract : 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.
|
Inhibition of Trypanosoma brucei FPPS
|
Trypanosoma brucei
|
300.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Farnesyl diphosphate synthase inhibitors with unique ligand-binding geometries.
Year : 2015
Volume : 6
Issue : 3
First Page : 349
Last Page : 354
Authors : Liu YL, Cao R, Wang Y, Oldfield E.
Abstract : Farnesyl diphosphate synthase (FPPS) is an important drug target for bone resorption, cancer, and some infectious diseases. Here, we report five new structures including two having unique bound ligand geometries. The diamidine inhibitor 7 binds to human FPPS close to the homoallylic (S2) and allosteric (S3) sites and extends into a new site, here called S4. With the bisphosphonate inhibitor 8, two molecules bind to Trypanosoma brucei FPPS, one molecule in the allylic site (S1) and the other close to S2, the first observation of two bisphosphonate molecules bound to FPPS. We also report the structures of apo-FPPS from T. brucei, together with two more bisphosphonate-bound structures (2,9), for purposes of comparison. The diamidine structure is of particular interest because 7 could represent a new lead for lipophilic FPPS inhibitors, while 8 has low micromolar activity against T. brucei, the causative agent of human African trypanosomiasis.
|
Inhibition of human FPPS in absence of pre-incubation of compound with enzyme
|
Homo sapiens
|
82.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Farnesyl diphosphate synthase inhibitors with unique ligand-binding geometries.
Year : 2015
Volume : 6
Issue : 3
First Page : 349
Last Page : 354
Authors : Liu YL, Cao R, Wang Y, Oldfield E.
Abstract : Farnesyl diphosphate synthase (FPPS) is an important drug target for bone resorption, cancer, and some infectious diseases. Here, we report five new structures including two having unique bound ligand geometries. The diamidine inhibitor 7 binds to human FPPS close to the homoallylic (S2) and allosteric (S3) sites and extends into a new site, here called S4. With the bisphosphonate inhibitor 8, two molecules bind to Trypanosoma brucei FPPS, one molecule in the allylic site (S1) and the other close to S2, the first observation of two bisphosphonate molecules bound to FPPS. We also report the structures of apo-FPPS from T. brucei, together with two more bisphosphonate-bound structures (2,9), for purposes of comparison. The diamidine structure is of particular interest because 7 could represent a new lead for lipophilic FPPS inhibitors, while 8 has low micromolar activity against T. brucei, the causative agent of human African trypanosomiasis.
|
Inhibition of human FPPS using pre-incubation of compound with enzyme
|
Homo sapiens
|
0.36
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Farnesyl diphosphate synthase inhibitors with unique ligand-binding geometries.
Year : 2015
Volume : 6
Issue : 3
First Page : 349
Last Page : 354
Authors : Liu YL, Cao R, Wang Y, Oldfield E.
Abstract : Farnesyl diphosphate synthase (FPPS) is an important drug target for bone resorption, cancer, and some infectious diseases. Here, we report five new structures including two having unique bound ligand geometries. The diamidine inhibitor 7 binds to human FPPS close to the homoallylic (S2) and allosteric (S3) sites and extends into a new site, here called S4. With the bisphosphonate inhibitor 8, two molecules bind to Trypanosoma brucei FPPS, one molecule in the allylic site (S1) and the other close to S2, the first observation of two bisphosphonate molecules bound to FPPS. We also report the structures of apo-FPPS from T. brucei, together with two more bisphosphonate-bound structures (2,9), for purposes of comparison. The diamidine structure is of particular interest because 7 could represent a new lead for lipophilic FPPS inhibitors, while 8 has low micromolar activity against T. brucei, the causative agent of human African trypanosomiasis.
|
Inhibition of recombinant human C-terminal His6-tagged GGPPS expressed in Escherichia coli BL21 at 100 uM using IPP and FPP as substrates pretreated for 15 mins followed by substrates addition and measured after 1 hr by colorimetric method relative to control
|
Homo sapiens
|
17.0
%
|
|
Journal : Eur J Med Chem
Title : Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis.
Year : 2018
Volume : 158
First Page : 184
Last Page : 200
Authors : Savino S, Toscano A, Purgatorio R, Profilo E, Laghezza A, Tortorella P, Angelelli M, Cellamare S, Scala R, Tricarico D, Marobbio CMT, Perna F, Vitale P, Agamennone M, Dimiccoli V, Tolomeo A, Scilimati A.
Abstract : Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC50 of 0.31 μM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.
|
Inhibition of recombinant human C-terminal His6-tagged FPPS expressed in Escherichia coli BL21 at 1 uM using DMAPP and IPP as substrates pretreated for 15 mins followed by substrates addition and measured after 1 hr by colorimetric method relative to control
|
Homo sapiens
|
93.5
%
|
|
Journal : Eur J Med Chem
Title : Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis.
Year : 2018
Volume : 158
First Page : 184
Last Page : 200
Authors : Savino S, Toscano A, Purgatorio R, Profilo E, Laghezza A, Tortorella P, Angelelli M, Cellamare S, Scala R, Tricarico D, Marobbio CMT, Perna F, Vitale P, Agamennone M, Dimiccoli V, Tolomeo A, Scilimati A.
Abstract : Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC50 of 0.31 μM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.
|
Inhibition of recombinant human C-terminal His6-tagged FPPS expressed in Escherichia coli BL21 using DMAPP and IPP as substrates pretreated for 15 mins followed by substrates addition and measured after 1 hr by colorimetric method
|
Homo sapiens
|
70.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis.
Year : 2018
Volume : 158
First Page : 184
Last Page : 200
Authors : Savino S, Toscano A, Purgatorio R, Profilo E, Laghezza A, Tortorella P, Angelelli M, Cellamare S, Scala R, Tricarico D, Marobbio CMT, Perna F, Vitale P, Agamennone M, Dimiccoli V, Tolomeo A, Scilimati A.
Abstract : Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC50 of 0.31 μM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.
|
Inhibition of FDPS (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel benzimidazole phosphonates as potential inhibitors of protein prenylation.
Year : 2019
Volume : 29
Issue : 24
First Page : 126757
Last Page : 126757
Authors : Bhuiyan NH, Varney ML, Wiemer DF, Holstein SA.
Abstract : Benzimidazole carboxyphosphonates and bisphosphonates have been prepared and evaluated for their activity as inhibitors of protein prenylation or isoprenoid biosynthesis. The nature of the phosphonate head group was found to dictate enzyme specificity. The lead carboxyphosphonate inhibits geranylgeranyl transferase II while its corresponding bisphosphonate analogue potently inhibits farnesyl diphosphate synthase. The most active inhibitors effectively disrupted protein prenylation in human multiple myeloma cells.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-4.82
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.02
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.02
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Binding affinity to BTN3A1 in human PBMC-derived Vgamma9/Vdelta2 T cells
|
Homo sapiens
|
80.0
nM
|
|
Journal : J Med Chem
Title : Aryloxy Diester Phosphonamidate Prodrugs of Phosphoantigens (ProPAgens) as Potent Activators of Vγ9/Vδ2 T-Cell Immune Responses.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 11258
Last Page : 11270
Authors : Kadri H,Taher TE,Xu Q,Sharif M,Ashby E,Bryan RT,Willcox BE,Mehellou Y
Abstract : Vγ9/Vδ2 T-cells are activated by pyrophosphate-containing small molecules known as phosphoantigens (PAgs). The presence of the pyrophosphate group in these PAgs has limited their drug-like properties because of its instability and polar nature. In this work, we report a novel and short Grubbs olefin metathesis-mediated synthesis of methylene and difluoromethylene monophosphonate derivatives of the PAg (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBP) as well as their aryloxy diester phosphonamidate prodrugs, termed ProPAgens. These prodrugs showed excellent stability in human serum (t > 12 h) and potent activation of Vγ9/Vδ2 T-cells (EC ranging from 5 fM to 73 nM), which translated into sub-nanomolar γδ T-cell-mediated eradication of bladder cancer cells in vitro. Additionally, a combination of in silico and in vitro enzymatic assays demonstrated the metabolism of these phosphonamidates to release the unmasked PAg monophosphonate species. Collectively, this work establishes HMBP monophosphonate ProPAgens as ideal candidates for further investigation as novel cancer immunotherapeutic agents.
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Inhibition of recombinant Leishmania major FPPS expressed in Escherichia coli BL21(DE3) using GPP and [14C]IPP as substrate incubated for 15 mins by scintillation counting method
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Leishmania major
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16.0
nM
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Journal : Bioorg Med Chem Lett
Title : A guanidinium-based inhibitor of a type I isopentenyl diphosphate isomerase.
Year : 2020
Volume : 30
Issue : 22
First Page : 127577
Last Page : 127577
Authors : Abdelmagid WM,Mahmoodi N,Tanner ME
Abstract : An inhibitor bearing a phosphinylphosphonate group appended to a guanidinium functionality was designed to inhibit enzymes that generate carbocations from dimethylallyl diphosphate. When tested against human farnesyl diphosphate synthase the inhibitor bound with high micromolar affinity and did not bind more tightly than an isosteric inhibitor lacking the guanidinium functionality. When tested against the Type I isopentenyl diphosphate:dimethylallyl diphosphate isomerase from Escherichia coli, the inhibitor bound with a K value of 120 nM, which was 400 times greater than its isosteric counterpart. This strategy of inhibition was much more effective with an enzyme that generates a carbocation that is not stabilized by both resonance and ion pairing, presumably because there is more evolutionary pressure on the enzyme to stabilize the cation.
