AZD5991

Catalog No.S8643

For research use only.

AZD5991 is a macrocyclic MCL-1 inhibitor with sub-nanomolar affinity for MCL-1 (Ki = 0.13 nM). The binding affinity of AZD5991 is about 25-fold lower for mouse Mcl-1 vs. human Mcl-1 but only four-fold lower for rat Mcl-1.

AZD5991 Chemical Structure

CAS No. 2143010-83-5

Selleck's AZD5991 has been cited by 10 Publications

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Biological Activity

Description AZD5991 is a macrocyclic MCL-1 inhibitor with sub-nanomolar affinity for MCL-1 (Ki = 0.13 nM). The binding affinity of AZD5991 is about 25-fold lower for mouse Mcl-1 vs. human Mcl-1 but only four-fold lower for rat Mcl-1.
Targets
Mcl-1 [2]
(Cell-free assay)
Mcl-1 [1]
(Cell-free assay)
0.13 nM(Ki) 0.7 nM
In vitro

AZD5991 is a potent and direct inhibitor of Mcl-1 with high selectivity versus other Bcl-2 family proteins. AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia (GI50 < 100nM), by activating the Bak-dependent mitochondrial apoptotic pathway. In a panel of cancer-derived cell lines of hematological or solid tumor origin, AZD5991 preferentially kills hematological cells[1][3].

Assay
Methods Test Index PMID
Western blot BCL2 / BCL-w / BCL-XL / MCL1 / BIM / BMF / p-ERK1/2 / ERK1/2 / PARP / β-actin / GAPDH ; BCL-XL / MCL1 / BIM / BMF / p-ERK1/2 / ERK1/2 / PARP / β-actin ; Caspase 3 / cPARP / Bak ; Mcl-1 / Bcl-2 / Bcl-Xl / Bim / cCaspase3 / Vinculin ; MCL1 / NOXA/ Vinc 31727888 30559424 32824203
Growth inhibition assay Tumor Volume ; Tumor Volume ; Cell Viability ; Cell Viability 31727888 30559424 33123685 33259592
In vivo

AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. In these in vivo studies, the cytotoxic activity of AZD5991 tightly correlates with induction of the mitochondrial apoptotic pathway as evidenced by cleavage of caspase-3 and PARP[1].

Protocol (from reference)

Cell Research:

[1]

  • Cell lines: MOLP-8 cells
  • Concentrations: 0-500 nM
  • Incubation Time: 30 min
  • Method:

    MOLP-8 cells are treated with AZD5991 or DMSO ontrol for 30 min. Then samples are centrifuged and pellet resuspended in ice-cold lysis buffer and incubated for 20 min on ice with vortexing every 5 min. Next, samples are centrifuged and protein concentration was assessed. Samples are pre-cleared for 30 min using rotation at 4 °C with 50% slurry of Protein A/G magnetic beads followed by incubation with anti-Mcl-1 antibody overnight at 4 °C with rotation. Protein A/G magnetic beads are then added for 1 h at 4 °C with rotation. Beads are washed four times with lysis buffer / PBS (1:1), then 10% sample reducing agent is added to each IP pellet followed by western blotting analysis.

Animal Research:

[1]

  • Animal Models: Subcutaneous MOLP-8 tumors model (Female C.B.-17 SCID mice)
  • Dosages: 10-100 mg/kg
  • Administration: IV

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight 672.26
Formula

C35H34ClN5O3S2

CAS No. 2143010-83-5
Storage 3 years -20°C powder
2 years -80°C in solvent
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

In vivo Formulation Calculator (Clear solution)

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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
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Molarity Calculator

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03218683 Suspended Drug: AZD5991|Drug: AZD5991 + Venetoclax Relapsed or Refractory Acute Myeloid Leukemia (AML) AstraZeneca August 14 2017 Phase 1|Phase 2

(data from https://clinicaltrials.gov, updated on 2022-08-01)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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