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| Targets |
GNE-064 targets the bromodomains of SMARCA4 (BRG1), SMARCA2 (BRM), and the fifth bromodomain of PBRM1 (BAF180). SMARCA2 and SMARCA4 are ATPase subunits of the SWI/SNF chromatin remodeling complex, which regulates gene expression by altering chromatin accessibility. PBRM1 is a subunit of the PBAF complex. By inhibiting these bromodomains, GNE-064 disrupts the function of SWI/SNF complexes, which are implicated in various cancers and neurological diseases.
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| ln Vitro |
When ZsGreen-SMARCA2 BD is expressed in U2OS cells, GNE-064 (0-0.5 μM; 1 hour) suppresses SMARCA2[1].
In vitro, GNE-064 inhibits SMARCA4 with an IC50 of 0.035 μM and inhibits SMARCA2 with an EC50 of 0.10 μM. It possesses Kd values of 0.01 μM for SMARCA4, 0.016 μM for SMARCA2, 0.018 μM for PBRM1 bromodomain 5, and 0.049 μM for PBRM1 bromodomain 2. GNE-064 (0-0.5 µM; 1 hour) inhibits SMARCA2 in ZsGreen-SMARCA2 BD-expressing U2OS cells. The compound's high solubility and selectivity make it useful as a chemical probe. |
| ln Vivo |
GNE-064 (Compound 5) (0.5 and 1.0 mg/kg; IV and PO once) displays optimal pharmacokinetic parameters in female CD-1 mice [1].
In vivo, GNE-064 is orally active and has potential applications in studying neurological diseases, particularly neurodegenerative conditions. Early studies suggest that GNE-064 could improve cognitive function and motor performance by addressing underlying pathophysiological mechanisms. The compound is being developed as a tool compound for research into SMARCA2/4 and PBRM1 biology. However, specific in vivo efficacy data have not been detailed in the available literature. |
| Enzyme Assay |
For in vitro binding assays, recombinant bromodomain proteins (SMARCA4, SMARCA2, PBRM1 BD5, PBRM1 BD2) are incubated with fluorescently labeled or radiolabeled ligands at various concentrations of GNE-064 (0.001-10 µM). Binding affinity (Kd) is determined using surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), or fluorescence polarization assays. IC50 and EC50 values are calculated by fitting dose-response curves.
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| Cell Assay |
Cell viability assay [1]
Cell Types: U2OS cells expressing ZsGreen-SMARCA2 BD Tested Concentrations: 0-0.5 μM Incubation Duration: 1 hour Experimental Results: Inhibition of SMARCA2 in U2OS cells expressing ZsGreen-SMARCA2 BD, EC50 is 0.1 μM. For cell-based assays, ZsGreen-SMARCA2 BD-expressing U2OS cells are treated with GNE-064 at concentrations ranging from 0-0.5 µM for 1 hour. SMARCA2 inhibition is assessed by measuring ZsGreen fluorescence or by Western blotting. Cell viability and proliferation can also be assessed. For epigenetic studies, effects on chromatin accessibility and gene expression can be evaluated by ATAC-seq or RNA-seq. |
| Animal Protocol |
Animal/Disease Models: Female CD-1 mice [1]
Doses: 0.5 mg/kg (iv) and 1.0 mg/kg (po) Route of Administration: intravenous (iv) (iv)injection and po (oral gavage); 0.5 mg/kg and 1.0 mg/kg once Experimental Results: Displayed low unbound plasma clearance of 16 mL/min/kg, a reasonable half-life of 1.1 hrs (hrs (hours)), and good oral bioavailability of 59%. For in vivo studies, animal models of neurological diseases or cancers driven by SWI/SNF alterations would be used. GNE-064 would be administered orally at doses determined from pharmacokinetic studies. Cognitive function, motor performance, and disease progression would be assessed depending on the model. However, specific in vivo protocols for GNE-064 have not been detailed in the available literature. |
| ADME/Pharmacokinetics |
GNE-064 is orally active and highly soluble. It is soluble in DMSO at ≥125 mg/mL (381.82 mM). For in vivo administration, it can be formulated as a clear solution in 5% DMSO + 40% PEG300 + 5% Tween-80 + 50% saline (≥4 mg/mL), or in 10% DMSO + 90% corn oil (≥2.08 mg/mL). Storage is recommended at -20°C for powder and -80°C for solutions. The compound is a chemical probe for research use only.
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| Toxicity/Toxicokinetics |
Toxicological data for GNE-064 have not been extensively reported. As a research compound, it is intended for laboratory use only and is not for human or veterinary use. Standard safety precautions should be followed when handling this compound. Comprehensive toxicology studies would be required before any clinical development.
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| References | |
| Additional Infomation |
GNE-064 is a selective, orally active, highly soluble inhibitor of SMARCA4, SMARCA2, and PBRM1 bromodomains. It inhibits SMARCA4 with IC50 of 0.035 μM and SMARCA2 with EC50 of 0.10 μM. GNE-064 is being developed as a chemical probe for studying epigenetic regulation, SWI/SNF complex biology, and potential applications in neurological diseases. It is a research tool and is not approved for clinical use.
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| Molecular Formula |
C17H21N5O2
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| Molecular Weight |
327.380943059921
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| Exact Mass |
327.169
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| CAS # |
1997321-20-6
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| PubChem CID |
137029447
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
0.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
24
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| Complexity |
449
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(C)N1CCN(C2=C(N)N=NC(C3C=CC=CC=3O)=C2)C[C@H]1C
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| InChi Key |
FHRKRGDHMCCDEO-LLVKDONJSA-N
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| InChi Code |
InChI=1S/C17H21N5O2/c1-11-10-21(7-8-22(11)12(2)23)15-9-14(19-20-17(15)18)13-5-3-4-6-16(13)24/h3-6,9,11,24H,7-8,10H2,1-2H3,(H2,18,20)/t11-/m1/s1
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| Chemical Name |
1-[(2R)-4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-2-methylpiperazin-1-yl]ethanone
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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 : ≥ 125 mg/mL (~381.82 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 4 mg/mL (12.22 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween-80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 4 mg/mL (12.22 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution. 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (6.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (20.8 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 4: ≥ 2.08 mg/mL (6.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution. Solubility in Formulation 5: ≥ 2.08 mg/mL (6.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (20.8 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0546 mL | 15.2728 mL | 30.5455 mL | |
| 5 mM | 0.6109 mL | 3.0546 mL | 6.1091 mL | |
| 10 mM | 0.3055 mL | 1.5273 mL | 3.0546 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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