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| Targets |
The primary target of Brigimadlin enantiomer (3081532-91-1) is MDM2 (murine double minute 2), an E3 ubiquitin ligase that negatively regulates the tumor suppressor protein p53. Under normal conditions, MDM2 binds to p53, promoting its ubiquitination and proteasomal degradation, thereby keeping p53 activity in check. In cancers with wild-type p53, MDM2 overexpression is a common mechanism of p53 inactivation. Brigimadlin functions as a selective MDM2 inhibitor, binding to the p53-binding pocket of MDM2 and preventing the MDM2-p53 interaction. This leads to stabilization and accumulation of p53, activation of p53-mediated transcription of target genes (such as p21, PUMA, and Bax), and induction of cell cycle arrest and apoptosis in cancer cells. Brigimadlin enantiomer is the enantiomer of the active compound (Brigimadlin) and may have reduced or altered MDM2 binding affinity. The parent compound Brigimadlin (BI 907828) is a highly potent MDM2 inhibitor (IC50 in the low nanomolar range).
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| ln Vitro |
In cell-free assays, the parent compound Brigimadlin (BI 907828) is a potent and selective MDM2 inhibitor. While specific IC50 values for Brigimadlin are not provided in the available literature, MDM2 inhibitors typically bind to the p53-binding pocket of MDM2 with high affinity (Kd values in the low nanomolar range, e.g., 1-20 nM). Selectivity for MDM2 over other proteins is a key characteristic of potent MDM2 inhibitors. The Brigimadlin enantiomer (3081532-91-1) is the enantiomer of the active compound and may have significantly reduced binding affinity for MDM2 if the active compound is stereospecific. No specific IC50 or binding affinity data are reported for the Brigimadlin enantiomer alone in the available literature. It is used as a control or reference standard in research.
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| ln Vivo |
In vitro, the parent compound Brigimadlin (BI 907828) exhibits anti-cancer activity by activating the p53 pathway. In cancer cells with wild-type p53, Brigimadlin treatment leads to p53 stabilization and accumulation, increased expression of p53 target genes (including p21, PUMA, Bax, and MDM2 itself), G1 and G2/M cell cycle arrest, and induction of apoptosis. Brigimadlin has demonstrated anti-proliferative activity in various cancer cell lines, including those with MDM2 amplification or overexpression. The Brigimadlin enantiomer (3081532-91-1) is the enantiomer of the active compound and may have reduced or no anti-cancer activity depending on stereospecificity. No specific in vitro data for the Brigimadlin enantiomer are reported in the available literature. It is primarily used for comparative studies to determine the stereospecificity of MDM2 binding and biological activity.
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| Enzyme Assay |
In vivo, the parent compound Brigimadlin (BI 907828) has anti-cancer activity and has been studied in preclinical xenograft models of MDM2-driven cancers. As an orally active MDM2 inhibitor, Brigimadlin is typically administered orally (by gavage) to tumor-bearing mice at doses ranging from 10-100 mg/kg daily or on a schedule (e.g., once daily for 2 weeks on, 1 week off). Endpoints include tumor growth inhibition (TGI), tumor regression, animal survival, p53 target gene activation in tumor tissue (by qRT-PCR, Western blotting), and immunohistochemistry for proliferation (Ki67) and apoptosis (cleaved caspase-3). The Brigimadlin enantiomer (3081532-91-1) is the enantiomer of the active compound and may have reduced or no in vivo anti-tumor activity. No specific in vivo data for the Brigimadlin enantiomer are reported in the available literature.
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| Cell Assay |
For Brigimadlin enantiomer and the parent compound, non-cell-based assays involve measuring the binding affinity of the compound to MDM2 protein. A typical assay: purified recombinant human MDM2 protein (usually the N-terminal p53-binding domain) is incubated with a fluorescently labeled p53-derived peptide (e.g., FITC-ETFSDLWKLLPEN) in assay buffer (20 mM Tris, pH 7.5, 100 mM NaCl, 5 mM DTT, 0.1% BSA). The test compound (Brigimadlin enantiomer) is added at varying concentrations (0.1 nM - 100 microM) to compete with the labeled peptide. After incubation at room temperature for 30-120 minutes, the fluorescence polarization (FP) or time-resolved fluorescence resonance energy transfer (TR-FRET) signal is measured. The IC50 (concentration that displaces 50% of the labeled peptide) is calculated from dose-response curves. For direct binding affinity (Kd), a fluorescently labeled Brigimadlin analog may be used in saturation binding experiments. Alternatively, surface plasmon resonance (SPR) can be used to measure real-time binding kinetics. For Brigimadlin enantiomer, these assays would determine its binding affinity relative to the active parent compound.
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| Animal Protocol |
For Brigimadlin enantiomer and the parent compound, cell-based assays typically use cancer cell lines with wild-type p53 and MDM2 amplification or overexpression (e.g., SJSA-1 osteosarcoma cells, which have amplified MDM2). Cells are cultured in RPMI 1640 or DMEM with 10% FBS and 1% penicillin/streptomycin at 37degC in 5% CO2. Cells are seeded in 96-well or 6-well plates, and after 24 hours, treated with test compound (0.1 nM - 10 microM) for 24-72 hours. Endpoints: cell viability (MTT, CellTiter-Glo, or clonogenic assays), p53 activation (Western blotting for p53, phospho-p53, and p53 target genes p21, MDM2, PUMA, Bax), cell cycle analysis (propidium iodide staining, flow cytometry), apoptosis (Annexin V/PI staining, caspase-3/7 activation, PARP cleavage, TUNEL). For Brigimadlin enantiomer, these assays would determine its anti-proliferative and p53-activating activity relative to the active parent compound. It is expected to have reduced activity if the parent compound is stereospecific.
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| ADME/Pharmacokinetics |
In vivo protocols for Brigimadlin enantiomer would typically use xenograft mouse models of MDM2-driven cancers. Immunocompromised mice (e.g., BALB/c nude mice, NOD/SCID mice, or athymic nude mice) are injected subcutaneously with cancer cells (e.g., SJSA-1 osteosarcoma cells, or other MDM2-amplified cancer cells, or patient-derived xenografts with MDM2 amplification). Once tumors reach ~100-200 mm3 (typically 7-14 days after implantation), the mice are randomized into treatment groups (n=6-10 per group). Brigimadlin enantiomer (or parent compound) is administered orally (by gavage) at doses ranging from 10-100 mg/kg daily or on a schedule (e.g., once daily for 2 weeks on, 1 week off). Vehicle control group receives the same volume of formulation (e.g., 0.5% methylcellulose + 0.2% Tween 80, or PEG400/water). Tumor volume is measured by calipers 2-3 times weekly. Body weight is measured to monitor toxicity. At the end of the study (typically 2-4 weeks), tumors are excised for PD analysis: p53 target gene expression (qRT-PCR, Western blotting), Ki67 immunohistochemistry (proliferation), and cleaved caspase-3 (apoptosis). Survival may be monitored as an endpoint for survival studies. For Brigimadlin enantiomer, it is expected to have reduced tumor growth inhibition compared to the active parent compound if the binding is stereospecific. No specific in vivo data for the Brigimadlin enantiomer are reported.
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| Toxicity/Toxicokinetics |
Not specifically reported for Brigimadlin enantiomer (3081532-91-1) in the available literature. The parent compound Brigimadlin (BI 907828) is described as orally active, indicating good oral absorption and bioavailability. Typical PK properties for MDM2 inhibitors include moderate to high oral bioavailability (30-70% in preclinical species), moderate plasma protein binding (likely >90%), moderate clearance (hepatic metabolism, likely CYP3A4-mediated), moderate half-life (2-8 hours in rodents), volume of distribution (1-2 L/kg), and good tumor penetration. Detailed PK parameters for Brigimadlin have not been provided. The Brigimadlin enantiomer may have distinct PK properties if the parent compound is used as a racemate, but stereospecific PK data are not reported. The enantiomer is not the active form and is used as a reference standard. It is not intended for PK studies as an active pharmaceutical.
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| References | |
| Additional Infomation |
Specific toxicity data for Brigimadlin enantiomer (3081532-91-1) are not reported in the available literature. The compound is intended for research use only and not for human therapeutic applications. As an MDM2 inhibitor, on-target toxicities of the parent compound could include p53 activation in normal tissues, leading to potential adverse effects such as myelosuppression (anemia, neutropenia, thrombocytopenia), gastrointestinal toxicity (nausea, vomiting, diarrhea), fatigue, and potentially other p53-mediated toxicities. Off-target effects on other proteins could contribute to additional toxicities. The Brigimadlin enantiomer is the enantiomer of the active compound; if the active compound is stereospecific, the enantiomer may have a different toxicity profile (potentially reduced toxicity due to lack of target engagement). No acute or chronic toxicity studies have been described for the enantiomer. Standard safety precautions for handling should be observed: use appropriate personal protective equipment, work in a fume hood, avoid inhalation or skin contact. The compound should be stored at -20degC as a powder, and at -80degC for solutions, protected from light and moisture. Purity specifications: typically >98% by HPLC. The compound is supplied as a small molecule solid for research use only.
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| Molecular Formula |
C31H25CL2FN4O3
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| Molecular Weight |
591.46
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| CAS # |
3081532-91-1
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| Related CAS # |
Brigimadlin; 2095116-40-6
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| Appearance |
White to off-white solid powder
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| SMILES |
O=C(O)C1=C(C2=NN3C(C[C@]([H])([C@]3([C@H]([C@@]45C(NC6=C5C=CC(Cl)=C6)=O)C7=C(C(Cl)=CC=C7)F)[H])N4CC8CC8)=C2C=C1)C
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| Synonyms |
BI 907828 enantiomer
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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 (~169.1 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.23 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 (25.0 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 | 1.6907 mL | 8.4537 mL | 16.9073 mL | |
| 5 mM | 0.3381 mL | 1.6907 mL | 3.3815 mL | |
| 10 mM | 0.1691 mL | 0.8454 mL | 1.6907 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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