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Purity: ≥98%
BI-7273 is a novel, potent, selective, and cell-permeable BRD9 inhibitor with IC50 and Kd of 19 and 0.75 nM, respectively; it also shows high effect on BRD7 with IC50 and Kd of 117 nM and 0.3 nM, respectively. BI-7273 may be useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings. Selective inhibitors of bromodomain-containing protein 9 (BRD9) may have therapeutic potential in the treatment of human malignancies and inflammatory diseases.
| Targets |
Bromodomain of BRD9 (IC50 = 19 nM in Alpha assay; Kd = 15.4 nM by ITC).
Bromodomain of BRD7 (IC50 = 117 nM in Alpha assay; Kd = 60 nM by ITC). Bromodomain of CECR2 (Kd = 2.3 µM by ITC). The compound is inactive (>100 µM) against BET family bromodomains (BRD4-BD1, BRD4-BD2, BRD2-BD1). |
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| ln Vitro |
having an IC50 and Kd of 19 and 0.75 nM, respectively, BI-7273 is a cell-permeable, selective inhibitor of BRD9. It also exhibits strong effects on BRD7, having an IC50 and Kd of 117 nM and 0.3 nM, respectively. With Kds of 8.8 nM, 210 nM, 2600 nM, and 8600 nM, respectively, BI-7273 is also marginally active against a set of kinases that includes CECR2, BRPF1, BRD1, CREBBP, EP300, FALZ, TAF1(2), and TAF1L(2). 1000 nM, 1200 nM, 850 nM, and 10,000 nM. The U2OS cell line exhibits activity with 1 μM of BI-7273. With an EC50 of 1400 nM, BI-7273 inhibits the growth of EOL-1 cells[1].
In a biochemical Alpha assay measuring inhibition of acetylated histone H3 binding to recombinant bromodomains, BI-7273 showed potent inhibition of BRD9 (IC50 = 19 nM) and BRD7 (IC50 = 117 nM), with no measurable activity against BRD4-BD1, BRD4-BD2, or BRD2-BD1 at concentrations up to 100 µM. Isothermal titration calorimetry (ITC) confirmed high-affinity binding to the BRD9 bromodomain (Kd = 15.4 nM). It also bound to BRD7 (Kd = 60 nM) and CECR2 (Kd = 2.3 µM). In a cellular fluorescence recovery after photobleaching (FRAP) assay using U2OS cells expressing a GFP-BRD9 fusion protein, BI-7273 (at 1 µM, the lowest concentration tested) showed 100% inhibition of BRD9 bromodomain chromatin binding. BI-7273 inhibited the proliferation of the human acute myeloid eosinophilic leukemia cell line EOL-1 with an EC50 of 1400 nM. In a panel of cancer cell lines, treatment with BI-7273 resulted in selective growth inhibition of a significant proportion of acute myeloid leukemia (AML) cell lines tested. BI-7273 treatment led to a potent but partial inhibition of MYC expression in AML cell lines. Domain-swap experiments in murine leukemia cells demonstrated that the antiproliferative activity of BI-7273 is mediated through its effect on the BRD9 bromodomain. Selectivity profiling against 48 bromodomains by differential scanning fluorimetry (DSF) identified only BRD9, BRD7, and CECR2 as targets with significant thermal shift at 10 µM. Kinase profiling at 10 µM showed inhibition below 40% against 31 kinases. |
| ln Vivo |
In a disseminated mouse model of AML using CIEA-NOG mice injected with luciferase-expressing EOL-1 cells, oral administration of BI-7273 (180 mg/kg, q.d.) demonstrated anti-leukemia activity. While specific tumor growth inhibition (TGI) data for BI-7273 is not separately reported in the main text (the efficacy figure focuses on compound 2/BI-9564), the article states that both compounds were explored for in vivo proof-of-concept, and the pharmacological properties allowed for such studies.
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| Enzyme Assay |
Alpha (Amplified Luminescent Proximity Homogeneous Assay) Screen: A biochemical assay was developed to measure the inhibitory effect of compounds on the binding between biotinylated acetylated histone H3 (or H4) peptide and GST-tagged bromodomains (BRD9, BRD7, BRD4-BD1, BRD4-BD2, BRD2-BD1). The assay utilizes streptavidin-coated donor beads and anti-GST acceptor beads. When the bromodomain-bound peptide brings the beads into proximity, a signal is generated upon laser excitation. Test compounds compete with the acetylated peptide for binding to the bromodomain, reducing the signal. Dose-response curves are generated to determine IC50 values.
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| Cell Assay |
Fluorescence Recovery After Photobleaching (FRAP) Assay: U2OS cells were transfected with a plasmid encoding a green fluorescent protein (GFP) fused to the full-length BRD9. Cells were treated with compounds or DMSO control, and also with the histone deacetylase inhibitor SAHA to increase the signal-to-noise ratio. A defined region of the nucleus was photobleached using a laser, and the recovery of fluorescence into the bleached area, which depends on the exchange of GFP-BRD9 with the chromatin-bound pool, was monitored over time. Inhibition of the bromodomain's acetyl-lysine binding function by compounds reduces its chromatin retention, leading to faster fluorescence recovery. Recovery half-times are calculated and compared to controls to assess cellular target engagement.
Cell Proliferation Assay (CellTiter-Glo): Cancer cell lines (e.g., EOL-1) were seeded in multi-well plates and treated with a dilution series of BI-7273 for a defined period (e.g., 3-5 days). Cell viability/proliferation was assessed by adding a luminescent cell viability reagent (CellTiter-Glo), which generates a signal proportional to the amount of ATP present, indicative of metabolically active cells. Luminescence was measured, and data was analyzed to calculate EC50 values. |
| Animal Protocol |
In Vivo Efficacy Study in Disseminated AML Model: Female CIEA-NOG immunodeficient mice were injected intravenously with 10^7 EOL-1 acute myeloid leukemia cells stably expressing luciferase. Treatment began on day 5 post-injection. Mice were orally administered either vehicle (0.5% Natrosol) or BI-7273 (180 mg/kg) daily (q.d.). Tumor burden was monitored periodically via bioluminescence imaging. Mice were sacrificed when disease burden exceeded a pre-specified grade, and survival was recorded. Body weight was monitored as an indicator of tolerability.
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| ADME/Pharmacokinetics |
It exhibits high water solubility at pH 6.8. The predicted hepatic clearance (CL) in mouse, rat, and human hepatocytes is moderate to high (expressed as a percentage of hepatic blood flow Qh). Plasma protein binding is low in mice, rats, and humans. No significant inhibition of major cytochrome P450 enzymes was observed. Caco-2 cell permeability assays showed moderate to high absorption permeability (Papp, A-to-B), but also increased efflux rate. Mouse pharmacokinetics (single dose): After intravenous bolus administration of 5 mg/kg, plasma clearance was moderate, and steady-state volume of distribution (Vss) was moderate. Following oral administration of 20 mg/kg, the area under the plasma concentration-time curve (AUC(0-last)) and maximum concentration (Cmax) were determined, indicating high oral bioavailability (F > 95%). After oral administration of a dose of 180 mg/kg, the drug exposure (AUC) increased, but the effect was not linearly proportional to the dose.
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| Toxicity/Toxicokinetics |
In cellular FRAP assays using U2OS cells, no compound-related toxicity was observed after 24 hours of treatment with BI-7273 at the tested concentration. In in vivo efficacy studies in mice, the weight loss observed in some animals was primarily attributed to increased tumor burden in the control group, but compound-related tolerance issues at high doses (180 mg/kg) cannot be completely ruled out. Specific organ toxicity or lethal dose data were not provided.
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| References | |
| Additional Infomation |
BI-7273 (Compound 1) is a chemical probe designed to selectively inhibit the bromine domain of the BRD9 subunit, a chromatin remodeling complex in the SWI/SNF pathway. It is based on a 2-methyl-2,7-naphthidium-1-one backbone, identified through fragment screening and virtual screening. The compound is designed to avoid pleiotropic effects caused by BET family inhibitors. It has a molecular weight of 353.4 Da and exhibits good ligand efficiency (LE = 0.41) and lipophilic ligand efficiency (LLE = 5.7). Due to its good potency, selectivity, and ADME/PK properties, this compound is suitable for in vitro and in vivo studies. It has been used to mimic BRD9 gene perturbations and investigate its function in acute myeloid leukemia (AML).
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| Molecular Formula |
C20H23N3O3
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|---|---|
| Molecular Weight |
353.4149
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| Exact Mass |
353.173
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| CAS # |
1883429-21-7
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| Related CAS # |
1883429-21-7; 2305379-66-0 (BRD7-IN-1 free base)
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| PubChem CID |
118796358
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
509.2±50.0 °C at 760 mmHg
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| Flash Point |
261.8±30.1 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.590
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| LogP |
1.85
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
522
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
RBUYFHLQNPJMQM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H23N3O3/c1-22(2)11-17-18(25-4)8-13(9-19(17)26-5)16-12-23(3)20(24)15-10-21-7-6-14(15)16/h6-10,12H,11H2,1-5H3
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| Chemical Name |
4-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one
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| Synonyms |
BI-7273; BI 7273; BI7273.
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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 : ~10 mg/mL (~28.30 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (2.83 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: 1 mg/mL (2.83 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 ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 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: ≥ 1 mg/mL (2.83 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 | 2.8296 mL | 14.1479 mL | 28.2957 mL | |
| 5 mM | 0.5659 mL | 2.8296 mL | 5.6591 mL | |
| 10 mM | 0.2830 mL | 1.4148 mL | 2.8296 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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