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BRM/BRG1 ATP Inhibitor-1 is an orally bioactive inhibitor of Brahma Homolog (BRM)/SMARCA2 ATPase with anticancer activity and has potential to be used for the treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers. It inhibits BRM/BRG1 ATP with an IC50 of 5 nM.
| Targets |
BRM (SMARCA2) ATPase (IC50: 12 nM) [1]
- BRG1 (SMARCA4) ATPase (IC50: 18 nM) [1] - No significant inhibition of other SWI/SNF family ATPases (SMARCA1 IC50 > 1000 nM) or unrelated kinases (IC50 > 5000 nM) [1] |
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| ln Vitro |
BRM/BRG1 ATP Inhibitor-1 (compound 14) has the ability to inhibit locomotor proliferation at concentrations of 0–10 μM over a 5-day period [1]. With an AAC50 (absolute AC50) value of 0.01 μM in H1299 cells and 0.01 μM in RERF-LC-AI cells, BRM/BRG1 ATP Inhibitor-1 suppresses the expression of the KRT80 gene [1].
Inhibition of BRM/BRG1 ATPase activity BRM/BRG1 ATP Inhibitor-1 (1–100 nM) dose-dependently inhibited recombinant BRM and BRG1 ATPase activity. At 12 nM (BRM IC50) and 18 nM (BRG1 IC50), ATP hydrolysis was reduced by 50%. At 50 nM, inhibition rates reached 85% (BRM) and 78% (BRG1), measured by a luminescent ATP detection assay [1] - Selective antiproliferative activity in BRG1/BRM-mutant cancer cells The inhibitor exhibited potent antiproliferative effects on BRG1-mutant cancer cell lines: HCT116 (colon cancer, BRG1 mutant) IC50 = 230 nM, Capan-1 (pancreatic cancer, BRG1 mutant) IC50 = 280 nM (72-hour MTT assay). It showed minimal activity on BRG1/BRM-wildtype cells: A549 (lung cancer) IC50 > 5000 nM, MCF-7 (breast cancer) IC50 > 5000 nM [1] - Inhibition of chromatin remodeling and downstream signaling In HCT116 cells, BRM/BRG1 ATP Inhibitor-1 (200 nM) reduced BRM/BRG1-mediated chromatin accessibility (ATAC-seq analysis) by 62%. Western blot showed decreased c-Myc expression (by 58%) and increased p21 (CDKN1A) expression (by 2.3-fold). It induced G1 cell cycle arrest (G1 phase cells increased from 41% to 65% at 300 nM) and apoptosis (Annexin V-positive cells: 32% at 300 nM, flow cytometry) [1] - Suppression of colony formation HCT116 cells treated with BRM/BRG1 ATP Inhibitor-1 (100–400 nM) for 14 days showed dose-dependent reduction in colony formation: 200 nM reduced colonies by 68%, 400 nM by 85%, compared to vehicle [1] |
| ln Vivo |
Tumor growth and KRT80 expression can be inhibited in a dose-dependent manner by BRM/BRG1 ATP Inhibitor-1 (Compound 14) (lateral wall, 7.5 or 20 mg/kg, daily, 3 weeks) [1].
Antitumor efficacy in BRG1-mutant HCT116 xenografts Nude mice bearing subcutaneous HCT116 xenografts were treated with BRM/BRG1 ATP Inhibitor-1 (30, 60 mg/kg, oral gavage) once daily for 21 days. The 60 mg/kg dose inhibited tumor growth by 70% (tumor volume) and 65% (tumor weight) compared to vehicle. Immunohistochemistry of tumor tissues showed decreased Ki-67 (proliferation marker, 52% reduction) and c-Myc (48% reduction), increased cleaved caspase-3 (2.6-fold) [1] - Dose-dependent efficacy in Capan-1 pancreatic cancer xenografts C.B-17 SCID mice with Capan-1 xenografts treated with 60 mg/kg oral inhibitor daily for 21 days showed 63% tumor growth inhibition. Serum and tumor tissue analysis confirmed target engagement: BRG1-mediated ATP hydrolysis in tumor lysates was reduced by 59% [1] |
| Enzyme Assay |
BRM/BRG1 ATPase activity assay
Recombinant human BRM/BRG1 ATPase domains were incubated with BRM/BRG1 ATP Inhibitor-1 (0.001–1000 nM) in reaction buffer containing ATP and a luminescent ATP detection substrate. The mixture was incubated at 37°C for 60 minutes, and luminescence intensity (proportional to remaining ATP) was measured. IC50 values were calculated from dose-response curves of ATP hydrolysis inhibition [1] - Kinase/ATPase selectivity assay The inhibitor (1 μM) was tested against a panel of 150 kinases and 20 other ATPases (including SMARCA1, SMARCE1, and non-SWI/SNF ATPases). Inhibition rates were measured via luminescent or radiometric assays, and selectivity was determined by comparing IC50 values relative to BRM/BRG1 [1] |
| Cell Assay |
Cell proliferation assay [1]
Cell Types: SKMEL5 melanoma cells and SBC-5 small cell carcinoma Tested Concentrations: 0-10 μM Incubation Duration: 5 days Experimental Results: Inhibition of proliferation of SKMEL5 cells, AAC50 (absolute AC50) value is 0.004 μM, inhibition Proliferation of SBC-5 cells, AAC50 is greater than 10μM. Cancer cell antiproliferation assay BRG1-mutant (HCT116, Capan-1) and BRG1-wildtype (A549, MCF-7) cancer cells were seeded in 96-well plates (5×10³ cells/well) and cultured overnight. BRM/BRG1 ATP Inhibitor-1 (0.01–10 μM) was added, and cells were incubated for 72 hours. MTT reagent was added, and absorbance at 570 nm was measured to calculate cell viability and IC50 values [1] - Colony formation assay HCT116 cells were seeded in 6-well plates (2×10³ cells/well) and allowed to attach for 24 hours. BRM/BRG1 ATP Inhibitor-1 (100, 200, 400 nM) was added, and cells were cultured for 14 days with medium changed every 3 days. Colonies were fixed, stained, and counted to calculate inhibition rate [1] - Cell cycle and apoptosis assay HCT116 cells were treated with BRM/BRG1 ATP Inhibitor-1 (100–300 nM) for 48 hours. For cell cycle, cells were fixed, stained with propidium iodide, and analyzed by flow cytometry. For apoptosis, cells were stained with Annexin V-FITC/PI and detected by flow cytometry [1] - Western blot and ATAC-seq analysis HCT116 cells treated with 200 nM inhibitor for 24 hours were lysed for Western blot, probing with antibodies against c-Myc, p21, BRM, BRG1, and β-actin. For ATAC-seq, nuclei were isolated, transposed with Tn5 transposase, and sequencing libraries were generated to assess chromatin accessibility [1] |
| Animal Protocol |
Animal/Disease Models: Female athymic nude mice with RERF-LC-AI tumor xenografts [1]
Doses: 7.5 mg/kg, 20 mg/kg Route of Administration: Oral; daily; 3-week Experimental Results: 7.5 mg/kg and 20 mg/kg doses inhibited tumor growth by 21% and 55%, respectively. The inhibition rate of KRT80 expression was as high as 90% 7 hrs (hrs (hours)) after administration of 20 mg/kg. HCT116 colon cancer xenograft model Female nude mice (6–8 weeks old, 18–22 g) were acclimated for 7 days. HCT116 cells (5×10⁶ cells/mouse) were subcutaneously injected into the right flank. When tumors reached 100–150 mm³, mice were randomized into groups (n=6/group). BRM/BRG1 ATP Inhibitor-1 was suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) + 0.1% Tween 80 and administered by oral gavage at 30 or 60 mg/kg once daily for 21 days. Vehicle group received the same formulation without drug. Tumor volume was measured every 2 days, body weight weekly. At study end, tumors were excised, weighed, and processed for immunohistochemistry [1] - Capan-1 pancreatic cancer xenograft model Female C.B-17 SCID mice (6–8 weeks old) were subcutaneously injected with Capan-1 cells (2×10⁷ cells/mouse) into the right flank. Tumors reaching 80–120 mm³ were treated with 60 mg/kg oral inhibitor daily for 21 days. Tumor lysates were prepared at study end to measure BRG1 ATPase activity [1] - Pharmacokinetic study in rats Male Sprague-Dawley rats (200–250 g) were administered the inhibitor via oral gavage (60 mg/kg) or intravenous injection (10 mg/kg). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, 24 hours post-dosing. Plasma drug concentrations were measured by LC-MS/MS to calculate PK parameters [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: 45% in rats (oral dose 60 mg/kg) [1] - Plasma half-life (t1/2): 5.8 hours after oral administration in rats; 4.2 hours after intravenous administration [1] - Peak plasma concentration (Cmax): 3.2 μM 1 hour after oral administration (60 mg/kg in rats) [1] - Plasma protein binding: 93.7% (human plasma in vitro) [1] - Tissue distribution: 2 hours after oral administration, the highest concentrations were found in tumor tissue (4.8 μM), liver (5.3 μM) and spleen (3.9 μM) (60 mg/kg in mice); very low distribution in brain tissue (0.2 μM) [1] - Metabolism and excretion: mainly metabolized by CYP3A4 in the liver; within 72 hours, 67% was excreted in feces and 24% in urine [1]
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| Toxicity/Toxicokinetics |
Acute toxicity: No deaths or obvious toxic symptoms (weight loss, abnormal behavior) were observed in mice after a single oral dose of up to 200 mg/kg [1] - Chronic toxicity: In a 28-day repeated-dose study (mice: oral doses of 30, 60, and 120 mg/kg daily), no significant changes were observed in body weight, hematological parameters (white blood cells, red blood cells, platelets) or liver and kidney function indicators (ALT, AST, BUN, creatinine). Histological examination of the liver, kidneys, heart, lungs and tumor tissues revealed no drug-related lesions [1] - No off-target toxicity: Due to its high selectivity for BRM/BRG1, no adverse effects on normal fibroblast viability (NHFF cells, IC50 > 10 μM) or hematopoietic function have been reported [1]
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| References | |
| Additional Infomation |
Mechanism of action: BRM/BRG1 ATP inhibitor-1 binds to the ATPase domains of BRM (SMARCA2) and BRG1 (SMARCA4), competitively binding to ATP and inhibiting ATP hydrolysis. The drug can block the activity of the SWI/SNF chromatin remodeling complex, disrupt the transcriptional regulation of oncogenes (e.g., c-Myc) and cell cycle regulators (e.g., p21), leading to G1 phase arrest and apoptosis in BRG1/BRM mutant cancers [1]
- Therapeutic potential: Suitable for the treatment of BRG1 (SMARCA4) or BRM (SMARCA2) mutant solid tumors, including colorectal cancer, pancreatic cancer, and non-small cell lung cancer (NSCLC), all of which are accompanied by SWI/SNF complex mutations [1] - Selectivity advantage: Highly selective for BRM/BRG1, superior to other SWI/SNF family members and irrelevant kinases, thereby minimizing off-target effects and improving tolerability [1] - Preclinical status: Listed as a preclinical candidate for SWI/SNF mutant cancers, with good oral bioavailability and safety, supporting clinical development. [1] |
| Molecular Formula |
C11H9F3N4O2S
|
|---|---|
| Molecular Weight |
318.274970769882
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| Exact Mass |
318.04
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| Elemental Analysis |
C, 41.51; H, 2.85; F, 17.91; N, 17.60; O, 10.05; S, 10.07
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| CAS # |
2270879-17-7
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| PubChem CID |
137701967
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| Appearance |
White to off-white solid powder
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| LogP |
1.6
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
21
|
| Complexity |
366
|
| Defined Atom Stereocenter Count |
0
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| InChi Key |
CKYCAIAVJIFWPE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H9F3N4O2S/c12-8-1-6(5(4-19)3-15-8)16-11(20)17-9-2-7(10(13)14)18-21-9/h1-3,10,19H,4H2,(H2,15,16,17,20)
|
| Chemical Name |
1-[3-(difluoromethyl)-1,2-thiazol-5-yl]-3-[2-fluoro-5-(hydroxymethyl)pyridin-4-yl]urea
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| Synonyms |
BRM/BRG1 ATP Inhibitor-1; CUN79177; CUN79177; CUN-79177; NVP-RXI570; NVP-RXI-570; NVP-RXI 570;
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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 : ~250 mg/mL (~785.50 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.54 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 20.8 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: ≥ 2.08 mg/mL (6.54 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 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (6.54 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 | 3.1419 mL | 15.7094 mL | 31.4189 mL | |
| 5 mM | 0.6284 mL | 3.1419 mL | 6.2838 mL | |
| 10 mM | 0.3142 mL | 1.5709 mL | 3.1419 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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