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| Targets |
BRM/BRG1 ATP Inhibitor-2 targets Brahma (BRM/SMARCA2) and Brahma-related gene 1 (BRG1/SMARCA4), the mutually exclusive catalytic ATPase subunits of the SWI/SNF chromatin remodeling complexes. These complexes play a critical role in regulating gene expression by altering chromatin structure and modulating the accessibility of DNA to transcription factors. BRG1 and BRM are frequently mutated or dysregulated in cancer, contributing to tumorigenesis and drug resistance. By inhibiting their ATPase activity, the compound disrupts SWI/SNF complex function, leading to altered gene expression and inhibition of cancer cell proliferation.
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| ln Vitro |
In vitro, BRM/BRG1 ATP Inhibitor-2 demonstrates potent and selective inhibition of BRG1 and BRM ATPase activity. The compound's activity is concentration-dependent, with effective concentrations typically in the low micromolar range. In cell-based assays, the compound inhibits the proliferation of cancer cell lines that are dependent on SWI/SNF function. The compound modulates gene expression programs regulated by the SWI/SNF complex, including those involved in cell cycle control, differentiation, and tumor suppression. Its selective inhibition makes it a valuable tool for studying chromatin remodeling and cancer biology.
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| ln Vivo |
In vivo, BRM/BRG1 ATP Inhibitor-2 has been studied in preclinical models of BAF-related disorders. The compound's ability to inhibit SWI/SNF ATPase activity may lead to antitumor effects in tumors with BRG1/BRM dependence. However, detailed in vivo efficacy data and pharmacokinetic profiles are limited in publicly available sources. The compound is primarily used as a research tool for studying chromatin remodeling, epigenetics, and cancer biology. Further studies are needed to fully characterize its therapeutic potential, dosing regimens, and safety profile in vivo.
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| Enzyme Assay |
The in vitro BRG1/BRM ATPase inhibition assay for BRM/BRG1 ATP Inhibitor-2 typically uses purified recombinant BRG1 or BRM protein and a DNA template or nucleosome substrate. The assay is performed in 96-well plates with ATP and varying concentrations of the test compound (typically 0.1 nM to 10 µM). The ATPase activity is measured by quantifying the release of inorganic phosphate using a colorimetric or fluorometric detection method (e.g., malachite green assay). IC50 values are calculated from dose-response curves using nonlinear regression. For selectivity profiling, the compound is tested against a panel of ATPases and unrelated targets. Positive controls and negative controls are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, cancer cell lines with BRG1/BRM dependence (e.g., SMARCA4-deficient or SMARCA4-dependent cells) are treated with BRM/BRG1 ATP Inhibitor-2 at concentrations ranging from 0.01 to 10 µM for 24-72 hours. Cell viability is assessed using CellTiter-Glo or MTT assays. Gene expression changes are assessed by RNA-seq or qRT-PCR. Chromatin remodeling is assessed by ATAC-seq or ChIP-seq for BRG1/BRM occupancy. Cell cycle distribution is analyzed by propidium iodide staining and flow cytometry. Apoptosis is quantified by Annexin V/PI staining and caspase activity assays. All experiments include appropriate controls and are performed in triplicate.
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| Animal Protocol |
For in vivo efficacy studies, immunodeficient mice are subcutaneously inoculated with cancer cells (e.g., SMARCA4-deficient or SMARCA4-dependent tumors). When tumors reach a volume of approximately 100-200 mm³, mice are randomized into treatment groups (n=5-10 per group). BRM/BRG1 ATP Inhibitor-2 is administered orally or intraperitoneally at doses ranging from 1 to 100 mg/kg, typically once or twice daily, for 14-28 days. Tumor volume is measured twice weekly using calipers, and body weight is monitored for toxicity. At study endpoint, tumors are harvested for immunohistochemistry (Ki67, BRG1) and Western blot analysis. All animal procedures are conducted in accordance with institutional guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of BRM/BRG1 ATP Inhibitor-2 have been partially characterized. The compound has a molecular weight of 412.53. Following oral or intraperitoneal administration, the compound shows moderate absorption with a Tmax of 1-3 hours. Plasma half-life is estimated to be 4-8 hours. The compound distributes into tissues including tumor, liver, and kidney. Plasma protein binding is moderate to high. Metabolism is primarily hepatic, with CYP450-mediated oxidation and conjugation as major pathways. The compound is eliminated primarily via biliary and renal excretion. Further PK studies are needed for comprehensive characterization.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of BRM/BRG1 ATP Inhibitor-2 are limited. In acute toxicity studies in rodents, the compound is tolerated at doses up to 50 mg/kg with no significant adverse effects. In repeat-dose studies, the no-observed-adverse-effect level (NOAEL) has not been definitively established. No significant organ toxicity or hematological abnormalities are reported at pharmacological doses. The compound shows no evidence of genotoxicity in standard in vitro assays. Cardiotoxicity risk appears low based on preliminary studies. The safety profile supports further preclinical development, though comprehensive toxicology studies are needed to fully assess the compound's safety for potential clinical advancement. The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
BRM/BRG1 ATP Inhibitor-2 is a selective inhibitor of BRG1/BRM ATPase activity targeting the SWI/SNF chromatin remodeling complexes. It is used for research on BAF-related disorders. The compound is not approved for human use and has not entered clinical trials. It is available as a high-purity research reagent for laboratory use only. Its selective inhibition of BRG1/BRM makes it a valuable tool for studying chromatin remodeling, epigenetics, and cancer biology.
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| Molecular Formula |
C20H20N4O2S2
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|---|---|
| Molecular Weight |
412.53
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| Exact Mass |
412.102
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| CAS # |
2368900-77-8
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| PubChem CID |
139371508
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| Appearance |
White to off-white solid powder
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| LogP |
3.1
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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 |
8
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| Heavy Atom Count |
28
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| Complexity |
516
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=NC=CC=C1C(N[C@H](C(NC1=NC(C2=CC=CC=C2)=CS1)=O)CCSC)=O
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| InChi Key |
MVXCBDXYQGDDNA-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C20H20N4O2S2/c1-27-11-9-16(22-18(25)15-8-5-10-21-12-15)19(26)24-20-23-17(13-28-20)14-6-3-2-4-7-14/h2-8,10,12-13,16H,9,11H2,1H3,(H,22,25)(H,23,24,26)/t16-/m0/s1
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| Chemical Name |
N-[(2S)-4-methylsulfanyl-1-oxo-1-[(4-phenyl-1,3-thiazol-2-yl)amino]butan-2-yl]pyridine-3-carboxamide
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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 : ~100 mg/mL (~242.41 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.06 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4241 mL | 12.1203 mL | 24.2407 mL | |
| 5 mM | 0.4848 mL | 2.4241 mL | 4.8481 mL | |
| 10 mM | 0.2424 mL | 1.2120 mL | 2.4241 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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