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| 25mg |
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Grassofermata (NAV-2729) is a selective ARF6 inhibitor (IC50 = 1.0 μM), or a dual inhibitor of Arf1/Arf6 activation, with anticancer effects. In a mouse model, uveal melanoma cell proliferation and tumorigenesis are reduced when ARF6 is blocked with a small-molecule inhibitor. This suggests a potential therapeutic approach for Gα-mediated diseases and validates the functional significance of this pathway.
| Targets |
Arf6; Arf
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|---|---|
| ln Vitro |
NAV-2729 binds to Arf6 directly. In contrast to Arf6's guanine nucleotide-binding pocket, NAV-2729 is thought to bind to Arf6 at the Arf6 GEF-binding area, according to a structural homology model of the Arf6/Arf6-GEF complex. On Arf6, NAV-2729 prevents guanine nucleotide exchange mediated by GEP100 and ARNO. The application of NAV-2729 to uveal melanoma cells inhibits the cells' ability to grow without anchorage[1]. NAV-2729 is a dual inhibitor of Arf1/Arf6, with a greater affinity for Arf1 than for Arf6. NAV-2729 inhibits both the cytohesin and BRAG-induced and spontaneous activation of Arf6. NAV-2729 is an inhibitor of Arf6's spontaneous activation and of Arf6's GEFs, BRAG2 and ARNO, activating it in solution. At a concentration of 25 μM, which is reported to produce nearly complete inhibition of both spontaneous and GEF-stimulated Arf6 activation in vitro, the inhibitory profile of NAV-2729 is examined. NAV-2729 impedes Δ13Arf6's spontaneous nucleotide exchange by about 15% under the assay conditions. A quarter of the activation of Δ13Arf6 by BRAG2Sec7PH is inhibited by NAV-2729. There is no detectable spontaneous nucleotide exchange in Δ17Arf1. NAV-2729 inhibits Δ17Arf1 activation by BRAG2Sec7PH with a significantly higher efficiency than Arf6 (50%). Nucleotide exchange rates are lowered by 50% in a dose-response experiment when using 10 μM NAV-2729 for Δ17Arf1, but not by 50% when using 25 μM NAV-2729 for Δ13Arf6.
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| ln Vivo |
In an orthotopic xenograft mouse model of uveal melanoma, systemic treatment of the mice with NAV-2729 inhibits tumorigenesis and tumor growth[1].
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| References |
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| Additional Infomation |
NAV2729 is a pyrazolopyrimidine that is 4H-pyrazolo[1,5-a]pyrimidin-7-one which is substituted at positions 2, 3, and 5 by benzyl, p-chlorophenyl, and p-nitrophenyl groups, respectively. It is an inhibitor of ADP-ribosylation factor 6 (ARF6), a member of the ADP ribosylation factor family of GTP-binding proteins. It has a role as an inhibitor. It is a pyrazolopyrimidine, a C-nitro compound and a member of monochlorobenzenes.
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| Molecular Formula |
C25H17CLN4O3
|
|---|---|
| Molecular Weight |
456.880484342575
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| Exact Mass |
456.098
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| Elemental Analysis |
C, 65.72; H, 3.75; Cl, 7.76; N, 12.26; O, 10.51
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| CAS # |
419547-11-8
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| Related CAS # |
419547-11-8;
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| PubChem CID |
2257249
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
5.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
871
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
WHYGBVWGARJOCS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H17ClN4O3/c26-19-10-6-18(7-11-19)24-22(14-16-4-2-1-3-5-16)28-29-23(31)15-21(27-25(24)29)17-8-12-20(13-9-17)30(32)33/h1-13,15,28H,14H2
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| Chemical Name |
2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)-1H-pyrazolo[1,5-a]pyrimidin-7-one
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| Synonyms |
Grassofermata; NAV 2729; NAV-2729; NAV2729
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~50 mg/mL (~109.4 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.55 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1888 mL | 10.9438 mL | 21.8876 mL | |
| 5 mM | 0.4378 mL | 2.1888 mL | 4.3775 mL | |
| 10 mM | 0.2189 mL | 1.0944 mL | 2.1888 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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