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Purity: ≥98%
AZD-5991 (AZD5991) is a novel, potent, rationally designed macrocyclic molecule and selective MCL-1 inhibitor with anticancer activity. With an IC50 of 0.7 nM in the FRET assay and a Kd of 0.17 nM in the surface plasmon resonance (SPR) assay, it inhibits MCL-1. The drug AZD5991, which is currently in clinical development, has a high affinity and selectivity for Mcl-1. By activating the Bak-dependent mitochondrial apoptotic pathway, AZD5991 binds directly to Mcl-1 and causes rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia. After a single well-tolerated dose, AZD5991 exhibits strong antitumor activity in vivo with complete tumor regression in a number of models of multiple myeloma and acute myeloid leukemia when used alone or in combination with bortezomib or venetoclax. A Phase I clinical trial (NCT03218683) has been started to evaluate AZD5991 in patients with hematological malignancies based on these encouraging data.
| Targets |
Mcl-1 (IC50 = 0.7 nM); Mcl-1 (Kd = 0.17 nM)
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| ln Vitro |
AZD5991 is a potent and direct inhibitor of Mcl-1 with high selectivity versus other Bcl-2 family proteins. Apoptosis is triggered quickly in cancer cells by AZD5991 by binding directly to Mcl-1 and activating the Bak-dependent mitochondrial apoptotic pathway, most notably in myeloma and acute myeloid leukemia (GI50 100nM) cells. Hematological cells are preferentially killed by AZD5991 in a panel of cancer-derived cell lines with hematological or solid tumor origins[1][3].
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| ln Vivo |
After a single well-tolerated dose, AZD5991 exhibits strong antitumor activity in vivo with complete tumor regression in a number of models of multiple myeloma and acute myeloid leukemia when used alone or in combination with bortezomib or venetoclax. As shown by the cleavage of caspase-3 and PARP in these in vivo studies, AZD5991's cytotoxic activity closely correlates with the activation of the mitochondrial apoptotic pathway[1].
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| Cell Assay |
MOLP-8 cells are treated with AZD5991 or DMSO ontrol for 30 min. The samples are then centrifuged, and the pellet is resuspended in ice-cold lysis buffer and incubated for 20 min.on ice with vortexing every 5 min. After centrifuging the samples, the protein concentration was measured. Before incubating with anti-Mcl-1 antibody overnight at 4 °C with rotation, samples are pre-cleared for 30 min at 4 °C using rotation and a 50% slurry of Protein A/G magnetic beads. After that, Protein A/G magnetic beads are added and rotated for 1 hour at 4 °C. Each IP pellet is given a 10% sample reducing agent addition before being washed four times with lysis buffer/PBS (1:1) and then being subjected to a western blotting analysis.
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| Animal Protocol |
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| References |
| Molecular Formula |
C35H34CLN5O3S2
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|---|---|
| Molecular Weight |
672.2592
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| Exact Mass |
671.18
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| Elemental Analysis |
C, 62.53; H, 5.10; Cl, 5.27; N, 10.42; O, 7.14; S, 9.54
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| CAS # |
2143061-81-6
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| Related CAS # |
AZD-5991 Racemate;2143010-83-5;AZD-5991 (S-enantiomer);2143061-82-7
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| Appearance |
Solid powder
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| SMILES |
CC1=C2C(=NN1C)CSCC3=NN(C(=C3)CSC4=CC5=CC=CC=C5C(=C4)OCCCC6=C(N(C7=C6C=CC(=C27)Cl)C)C(=O)O)C
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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; AZD-5991; AZD5991
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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: 100~250 mg/mL (148.8~371.9 mM）
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.09 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 (3.09 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. View More
Solubility in Formulation 3: 2.08 mg/mL (3.09 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. Solubility in Formulation 4: 2.08 mg/mL (3.09 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 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. Solubility in Formulation 5: ≥ 2.08 mg/mL (3.09 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 6: ≥ 2.08 mg/mL (3.09 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. |
| 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03218683 | Terminated | Drug: AZD5991 + Venetoclax Drug: AZD5991 |
Relapsed or Refractory Acute Myeloid Leukemia (AML) |
AstraZeneca | August 2, 2017 | Phase 1 |
Hematological cell lines are preferentially sensitive to AZD5991. |
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AZD5991 causes tumor regression in AML models.Nat Commun.2018 Dec 17;9(1):5341. |
AZD5991 exhibits potent anti-tumor efficacy in MM models.Nat Commun.2018 Dec 17;9(1):5341. |
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