| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
Mcl-1 (Ki = 0.13 nM); Mcl-1 (IC50 = 0.7 nM)
AZD-5991 Racemate targets Mcl-1 (myeloid cell leukemia 1), an anti-apoptotic protein in the Bcl-2 family. Mcl-1 is frequently overexpressed in various cancers and contributes to chemoresistance by sequestering pro-apoptotic proteins such as Bak and Bax. By binding directly to Mcl-1, AZD-5991 disrupts the interaction between Mcl-1 and Bak, freeing Bak to activate the mitochondrial apoptotic pathway. The compound has an IC50 of <3 nM in a FRET assay. |
|---|---|
| ln Vitro |
AZD5991 is a potent and direct inhibitor of Mcl-1 with high selectivity versus other Bcl-2 family proteins. Inducing rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia (GI50 < 100 nM), AZD5991 binds directly to Mcl-1 and activates the Bak-dependent mitochondrial apoptotic pathway. AZD5991 kills hematological cells more frequently than solid tumor cells in a panel of cancer-derived cell lines[1][3].
In vitro, AZD-5991 Racemate demonstrates potent inhibition of Mcl-1 with an IC50 of <3 nM in a FRET assay. It induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia (GI50 < 100 nM). The compound shows high selectivity for Mcl-1 over other Bcl-2 family proteins. In AML cell lines, AZD-5991 induces upregulation of BCL2, BCL-XL, CMYC, and MCL1. The compound's direct binding to Mcl-1 activates the Bak-dependent mitochondrial apoptotic pathway. |
| ln Vivo |
After a single well-tolerated dose as monotherapy or in combination with bortezomib or venetoclax, AZD5991 exhibits significant antitumor activity in vivo with complete tumor regression in a number of models of multiple myeloma and acute myeloid leukemia. Cleavage of caspase-3 and PARP in these in vivo studies showed a strong correlation between AZD5991's cytotoxic activity and the activation of the mitochondrial apoptotic pathway[1].
Specific in vivo activity data for AZD-5991 Racemate are not detailed in the available sources. As a potent Mcl-1 inhibitor with potent activity against myeloma and AML cells in vitro, the compound is expected to have in vivo efficacy in xenograft models of these cancers. However, specific animal model studies have not been described in the available literature. The compound is intended for research use only. |
| Enzyme Assay |
The Mcl-1 inhibition assay for AZD-5991 Racemate is performed using a FRET (fluorescence resonance energy transfer) assay. Recombinant Mcl-1 protein and a labeled peptide corresponding to the Bak BH3 domain are incubated with varying concentrations of the compound. The FRET signal is measured, and the IC50 for inhibition of the Mcl-1/Bak interaction is calculated. Alternatively, surface plasmon resonance (SPR) can be used to measure the direct binding affinity (Kd) of the compound to Mcl-1.
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| Cell Assay |
MOLP-8 cells are treated with AZD5991 or DMSO ontrol for 30 min. AZD5991 or DMSO ontrol are applied to MOLP-8 cells. The samples are then centrifuged, and the pellet is resuspended in ice-cold lysis buffer and incubated for 20 minutes on ice while vortexing every five minutes. After samples have been centrifuged, the protein concentration has been determined. Prior to overnight incubation with anti-Mcl-1 antibody at 4 °C with rotation, samples are pre-cleared for 30 min using rotation and a 50% slurry of Protein A/G magnetic beads. The next step is to add Protein A/G magnetic beads, which are rotated for 1 hour at 4 °C. Each IP pellet is then given a 10% sample reducing agent addition and four PBS:lysis buffer washes before being subjected to a western blotting analysis.
To evaluate the cellular activity of AZD-5991 Racemate, cancer cell lines (such as myeloma or AML cell lines) are seeded in 96-well plates and treated with varying concentrations of AZD-5991. After 48-72 hours of incubation, cell viability is measured using an MTT or CellTiter-Glo assay. The GI50 (concentration causing 50% growth inhibition) is calculated. Apoptosis induction is assessed by measuring caspase activity or using annexin V-FITC staining and flow cytometry. The compound's effect on Mcl-1 and Bak interaction can be assessed by co-immunoprecipitation or proximity ligation assays. |
| Animal Protocol |
Mice and Rats[1] In mice, drugs (e.g., AZD5991; 10-100 mg/kg) are dosed intravenously in a volume of 5 mL/kg except for Venetoclax that is dosed orally in a volume of 10 mL/kg. One million MV4-11, five million MOLP-8, ten million NCI-H929 or five million OCI-AML3 cells are injected subcutaneously in the right flank of mice in a volume of 0.1 mL. In rats, AZD5991 (10-100 mg/kg) is dosed intravenously in a volume of 10 mL/kg. Ten million MV4-11 cells are injected subcutaneously in the right flank of rats in a volume of 0.1 mL. Tumor volumes (measured by caliper), animal body weight, and tumor condition are recorded twice weekly for the duration of the study. The tumor volume is calculated[1].
Specific in vivo animal experiment protocols for AZD-5991 Racemate are not detailed in the available sources. As an Mcl-1 inhibitor with potent activity against myeloma and AML cells, the compound would typically be evaluated in xenograft models using human cancer cell lines implanted subcutaneously into immunodeficient mice. AZD-5991 would be administered intravenously or intraperitoneally, and tumor growth inhibition would be measured. However, specific protocols are not described in the available literature. |
| ADME/Pharmacokinetics |
Specific pharmacokinetic data for AZD-5991 Racemate are not provided in the available sources. The compound is a small molecule with a molecular weight of 672.26 and a molecular formula of C35H34ClN5O3S2. As a racemic mixture, it contains both enantiomers of AZD-5991. Standard pharmacokinetic studies would typically involve administering the compound to rodents and measuring plasma concentrations over time using LC-MS/MS to determine key PK parameters.
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| Toxicity/Toxicokinetics |
Specific toxicity data for AZD-5991 Racemate are not provided in the available sources. As a research compound, it is intended for laboratory use only and is not approved for human therapeutic applications. The compound is a potent Mcl-1 inhibitor, and its toxicity profile would be expected to reflect its mechanism of action, potentially including effects on normal cells that depend on Mcl-1 for survival. Standard safety precautions should be followed when handling this compound.
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| References | |
| Additional Infomation |
AZD-5991 is currently undergoing clinical trial NCT03218683 (Study on AZD5991 for the treatment of relapsed or refractory hematologic malignancies).
AZD5991, a Mcl-1 inhibitor, is an inhibitor of differentiation proteins inducible myeloid leukemia cells (Myeloid Leukemia-1; Mcl-1; Bcl2-L-3) with potential pro-apoptotic and anti-tumor activities. After administration, AZD5991 binds to Mcl-1, thereby preventing Mcl-1 from binding to and inactivating certain pro-apoptotic proteins, and promoting apoptosis in Mcl-1-overexpressing cells. Mcl-1 is an anti-apoptotic protein belonging to the Bcl-2 protein family, upregulated in cancer cells, and promotes tumor cell survival. AZD-5991 Racemate is the racemic form of AZD-5991, a potent and direct inhibitor of Mcl-1 with high selectivity versus other Bcl-2 family proteins. It has an IC50 of <3 nM in a FRET assay and induces rapid apoptosis in cancer cells, most notably myeloma and AML (GI50 < 100 nM). The compound binds directly to Mcl-1 and activates the Bak-dependent mitochondrial apoptotic pathway. It has a molecular formula of C35H34ClN5O3S2 and a molecular weight of 672.26. |
| Molecular Formula |
C35H34CLN5O3S2
|
|---|---|
| Molecular Weight |
672.2592
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| Exact Mass |
671.179
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| CAS # |
2143010-83-5
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| Related CAS # |
AZD-5991;2143061-81-6;AZD-5991 (S-enantiomer);2143061-82-7
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| PubChem CID |
131634760
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.42±0.1 g/cm3(Predicted)
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| Boiling Point |
949.6±65.0 °C(Predicted)
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| LogP |
6.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
46
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| Complexity |
1060
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC2C3CCCOC4=CC(=CC5=CC=CC=C45)SCC4=CC(CSCC5C(=C(C)N(C)N=5)C=1C=2N(C)C=3C(=O)O)=NN4C
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| InChi Key |
KBQCEQAXHPIRTF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C35H34ClN5O3S2/c1-20-31-29(38-40(20)3)19-45-17-22-15-23(41(4)37-22)18-46-24-14-21-8-5-6-9-25(21)30(16-24)44-13-7-10-26-27-11-12-28(36)32(31)33(27)39(2)34(26)35(42)43/h5-6,8-9,11-12,14-16H,7,10,13,17-19H2,1-4H3,(H,42,43)
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| Chemical Name |
17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(36),4(38),6,11,14,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylic acid
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| Synonyms |
AZD-5991 racemate; AZD5991; AZD 5991 racemate
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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 (~148.8 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4875 mL | 7.4376 mL | 14.8752 mL | |
| 5 mM | 0.2975 mL | 1.4875 mL | 2.9750 mL | |
| 10 mM | 0.1488 mL | 0.7438 mL | 1.4875 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.
Link: https://clinicaltrials.gov/ct2/show/NCT03013998
Conditions:Previously Untreated Relapsed Refractory Acute Myeloid LeukemiaLink: https://clinicaltrials.gov/ct2/show/NCT03218683
Conditions:Relapsed or Refractory Acute Myeloid Leukemia (AML)
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