AZD5991

For research use only.

Catalog No.S8643

4 publications

AZD5991 Chemical Structure

CAS No. 2143010-83-5

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.

Selleck's AZD5991 has been cited by 4 publications

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Choose Selective Bcl-2 Inhibitors

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; 

PubMed: 31727888     


c. A375 cells were treated with the indicated concentrations of AZD5991 with or without 1 μM vemurafenib (Vem) for 24 h. d. SK-MEL-30 cells were treated with the indicated concentrations of AZD5991 with or without 1 μM selumetinib (Sel) for 24 h.

BCL-XL / MCL1 / BIM / BMF / p-ERK1/2 / ERK1/2 / PARP / β-actin; 

PubMed: 31727888     


a. A375 cells were treated with DMSO vehicle-only (C and 5991) or 2 μM vemurafenib (Vem and Vem + 5991) for 24 h followed by DMSO-only (C and Vem) or 1 μM AZD5991 (5991 and Vem + 5991) for a further 4 h. Lysates (input) were subjected to immunoprecipitation with antibodies to BCL-XL or MCL1. Input lysates, immunoprecipitates (IP) and supernatant unbound fractions (UNB) were then western blotted using the indicated antibodies.

Caspase 3 / cPARP / Bak; 

PubMed: 30559424     


b. MV4-11 tumor lysates prepared from mice dosed with a single i.v. dose of AZD5991 at 30 mg kg−1 (n = 4), 100 mg kg−1 (n = 4), or vehicle control (n = 2) were evaluated for expression of caspase 3 and cleaved PARP by western blotting. Leukemic cells (HLA-ABC+ hCD45+) were assessed by flow cytometry in peripheral blood.

Mcl-1 / Bcl-2 / Bcl-Xl / Bim / cCaspase3 / Vinculin; 

PubMed: 30559424     


f. OCI-AML3 whole-cell lysates prepared before or after 3, 6, or 24 h of treatment with venetoclax, AZD5991, or combination were evaluated for expression of indicated proteins by immunoblotting.

MCL1 / NOXA/ Vinc; 

PubMed: 32824203     


(A) The indicated cell lines were incubated with AZD5991 for 24 h and analyzed for NOXA and MCL1 protein expression. A 6 h incubation of AT101 (AT) was used as a positive control for NOXA induction.

31727888 30559424 32824203
Growth inhibition assay
Tumor Volume; 

PubMed: 31727888     


d, e Female nude athymic mice were implanted subcutaneously with A375 cells and randomised 21 days later for dosing with either vehicle-only (Control, n = 5), 25 mg kg−1 selumetinib (Sel, n = 7) twice daily with an 8 h interval, 60 mg kg−1 AZD5991 (n = 7) intravenously once weekly, or the combination of 25 mg kg−1 selumetinib and 60 mg kg−1 AZD5991 (Sel + AZD5991, n = 8) for a further 21 days. Tumour growth was recorded twice weekly and results are mean ± SEM (d) or mean % change in tumour volume ± SEM (e).

Tumor Volume; 

PubMed: 30559424     


AZD5991 exhibits potent anti-tumor efficacy in MM models. a Subcutaneous tumor growth in the MOLP-8 tumor model treated with a single i.v. dose of AZD5991 10–100 mg kg−1. Tumor volumes are presented as mean ± SEM, seven mice were evaluated per group.

Cell Viability; 

PubMed: 33123685     


d-e, Representative graphs depict the viabilities (mean from 3 technical replicates) of Molm13 cells expressing PTPN11 WT or A72D in the presence or absence of AZD5991. The upper panel d, is the constitutive transduction system, and the bottom e, is the Dox inducible transduction system.

Cell Viability; 

PubMed: 33259592     


(F) Cell viability of Bfl-1− (blue) or Bfl-1+ (red) cell lines in response to a dose response of AZD5991 treated for 24 hours.

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

Cell Research:

[1]

- Collapse
  • 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.


    (Only for Reference)
Animal Research:

[1]

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

Solubility (25°C)

In vitro DMSO 100 mg/mL (148.75 mM)
Water Insoluble
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 672.26
Formula

C35H34ClN5O3S2

CAS No. 2143010-83-5
Storage powder
in solvent
Synonyms N/A
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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Clinical Trial Information

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

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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Bcl-2 Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID