AZD-5153 6-hydroxy-2-naphthoic acid

For research use only.

Catalog No.S8344 Synonyms: AZD-5153 HNT salt

6 publications

AZD-5153 6-hydroxy-2-naphthoic acid Chemical Structure

CAS No. 1869912-40-2

AZD-5153 6-hydroxy-2-naphthoic acid (HNT salt) is a potent, selective, and orally available BET/BRD4 bromodomain inhibitor with pKi of 8.3 for BRD4. AZD-5153 inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes. NSD3, via H3K36me2, acts as an epigenetic deregulator to facilitate the expression of oncogenesis-promoting genes.

Selleck's AZD-5153 6-hydroxy-2-naphthoic acid has been cited by 6 publications

Purity & Quality Control

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Biological Activity

Description AZD-5153 6-hydroxy-2-naphthoic acid (HNT salt) is a potent, selective, and orally available BET/BRD4 bromodomain inhibitor with pKi of 8.3 for BRD4. AZD-5153 inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes. NSD3, via H3K36me2, acts as an epigenetic deregulator to facilitate the expression of oncogenesis-promoting genes.
Targets
FL-BRD4 [1]
(Cell-based assay)
5 nM
In vitro

Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. AZD5153 potently disrupts BRD4 foci in U2OS cells with an IC50 value of 1.7 nmol/L. AZD5153 efficiently downregulates MYC protein levels across the cell line panel irrespective of their sensitivity to AZD5153. AML, MM, and DLBCL cell lines are highly sensitive to AZD5153[1].

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
HCT116 NV\qepQ4TnWwY4Tpc44h[XO|YYm= NWH1blhKOThiaILz NWXZN2ZPTGm|cHzhZ4Vu\W62IH;mJGhidG9vdHHn[4VlKGirc4TvcoUhUDNwMzDmdo9uKE6jbn;MeYMufGGpZ3XkJIZ2dGxibHXu[5RpKEKURESgLJVvc26xd36gc5Jq\2mwKTDlfJBz\XO|ZXSgbY4hUEOWMUG2JINmdGy|IHHmeIVzKDF6IHjyd{BjgSCQYX7vRnJGXCCjc4PhfeKhNCCLQ{WwJF0hOC5yMEWg{txONg>? NGXMR2s9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OEG5OVczOyd-MkixPVU4OjN:L3G+
HCT116 MYXGeY5kfGmxbjDhd5NigQ>? NH7iSWkyQCCqcoO= NFfWepNFcXOybHHj[Y1mdnRib3[gTIFtdy22YXfn[YQhcGm|dH;u[UBJOy5|IH\yc40hVi22ZYLtbY5idCCQYX7vUJVkNXSjZ3fl[EBDWkR2IHLyc41w\G:vYXnuJFEhMDR2IITvJFE3QCC{ZYPp[JVmeyliKIXub45wf25ib4Lp[4lvMSCneIDy[ZN{\WRiaX6gTGNVOTF4IHPlcIx{KGGodHXyJFE5KGi{czDifUBP[W6xQmLFWEBie3OjedMgMEBKSzVyIE2gNU43KM7:TT6= MYm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQDF7NUeyN{c,OjhzOUW3NlM9N2F-

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
NRG1 / BRD4 / GAPDH; 

PubMed: 30036377     


(B) NRG1 protein levels measured by immunoblot in OV0857F tumors at 4 hr and 24 hr following a single or 4-repeat p.o. dose of 10 mg/kg AZD5153.

NRG1 / BRD4 / GAPDH; 

PubMed: 30036377     


(D) NRG1 protein levels measured by immunoblot in HOXF062 tumors at 4 hr following a single p.o. dose of 30 mg/kg AZD5153.

NRG1 / BRD4 / GAPDH; 

PubMed: 30036377     


(F) NRG1 protein levels measured by immunoblot in OV2022F tumors at 4 hr following either 10 mg/kg QD or 5 mg/kg BIDx3 AZD5153.

BRD4 / C-MYC / GAPDH; 

PubMed: 31523195     


BRD4 Inhibition Suppresses Human Colorectal Cancer Cell Proliferation. Western blot analysis of expression of BRD4 and c-Myc after treatment with AZD5153 in HCT116 and LoVo cells.

cle-PARP / cle-caspase3 / GAPDH; 

PubMed: 31523195     


C) Western blot analysis of expression of cleaved-poly(ADP-ribose) polymerase (PARP) and cleaved-caspase-3 in HCT116 and LoVo cells treated with vehicle (0.01% dimethyl sulfoxide (DMSO)), AZD5153.

Wee1 / CDK1 / p-CDK1 / GAPDH; 

PubMed: 31523195     


B) AZD5153 inhibited the expression of Wee1 and phosphorylation of CDK1 in HCT116 and Love cells.

30036377 31523195
Growth inhibition assay
Tumor Volume / Body Weight; 

PubMed: 29636547     


Concurrent BET and ATR inhibition inhibits ovarian tumor growth in vivo. A. OVCAR3 cells were injected subcutaneously into C.B.−17 scid mice and allowed to grow for 6 days. Tumor-bearing mice randomized into the following treatment groups (n = 10/group) were orally administered vehicle once daily, 2.5 mg/kg AZD5153 once daily, 25 mg/kg AZD6738 once daily, or a combination of AZD5153 and AZD6738 once daily for 21 days. Data values for tumor volumes are represented as geometric mean ± SEM. Data values for % body weight change are represented as mean ± SEM of each treatment group.

29636547
IHC
cle-caspase3 / cle-PARP / Ki-67; 

PubMed: 31523195     


AZD5153 improves therapeutic efficacy of the PARP inhibitor, BMN673, in colorectal cancer cells in vivo. Male and female nude mice (n = 6 per group) were orthotopically implanted with HCT116 tumor xenografts and given treatment with a vehicle control, AZD5153 (5 mg/kg), BMN673 (0.33mg/kg), or a combination of these two agents via oral gavage for 3 weeks. E) Representative images of H&E, Ki-67, cleaved-poly(ADP-ribose) polymerase (PARP), and cleaved-caspase-3 immunohistochemistry.

31523195
Immunofluorescence
CDC6 p-S54; 

PubMed: 29636547     


C. Representative images of U2OS cells stained for phospho-CDC6 (S54) with or without 2-hour AZD5153 treatment (500 nM). Selective regions are zoomed in to show phospho-CDC6 foci.

29636547
ELISA
IL-10 / IL-12; 

PubMed: 32184777     


(B) ELISA evaluation of IL-10 and IL-12 for M2 macrophages treated with and without AZD5153. Left: experiments in THP-1 (n = 3). Right: experiments for healthy female peripheral blood macrophages (n = 5). Data represent mean ± SEM. *P < 0.05.

32184777
In vivo In vivo administration of AZD5153 leads to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. AZD5153 modulates MYC and HEXIM1 in AML xenograft tumors and human whole blood[1]. AZD5153 is administered orally to mice bearing MV-4-11 xenografts, and pharmacodynamic activity (intratumoral levels of c-Myc) is measured at 2, 4, and 8 h postdose. A considerable decrease in c-Myc expression is observed out to 8 h post dose at free plasma levels of compound <0.2 μM. This decrease in c-Myc expression after treatment with AZD5153 is consistent with other published BET inhibitors[2].

Protocol

Cell Research:

[1]

- Collapse
  • Cell lines: MV-4-11, MM.1S, and K562 cells
  • Concentrations: --
  • Incubation Time: 48 h
  • Method:

    Apoptosis was analyzed by flow cytometry using CellEvent Caspase 3/7 Green detection reagent. MV-4-11, MM.1S, and K562 cells were pretreated with AZD5153 or I-BET762 for 48 hours in culture media. Cells were collected and stained with 5 μmol/L final concentration of CellEvent for 30 minutes at 37°C. Flow cytometry was done on a BD Fortessa using the Blue laser and FITC filter set.


    (Only for Reference)
Animal Research:

[1]

- Collapse
  • Animal Models: Female CB17 SCID and SCID beige mice
  • Dosages: --
  • Administration: by oral gavage mini-pump infusion or s.c
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (149.75 mM)
Water Insoluble
Ethanol ''''''27 mg/mL warmed

* 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 667.75
Formula

C25H33N7O3.C11H8O3

CAS No. 1869912-40-2
Storage powder
in solvent
Synonyms AZD-5153 HNT salt
Smiles CC1C(=O)N(CCN1CCOC2=CC=C(C=C2)C3CCN(CC3)C4=NN5C(=NN=C5OC)C=C4)C.C1=CC2=C(C=CC(=C2)O)C=C1C(=O)O

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03205176 Completed Drug: AZD5153|Drug: Olaparib Malignant Solid Tumors|Lymphoma|Ovarian Cancer|Breast Cancer|Pancreatic Cancer|Prostate Cancer AstraZeneca June 30 2017 Phase 1

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Epigenetic Reader Domain Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID