AZD9496

Protein target name:

ESR1

Mechanism of action:

AntagonistDownregulatorInhibitor

Recommended Concentration for use in cells:

< 10 nM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Nuclear Hormone Receptor

Subclass:

NR3 Subfamily

HUGO ID:

HGNC:3467

Entrez gene ID:

2099

UNIPROT ID:

P03372

Target alias:

ER; ESR; Era; ESRA; ESTRR; NR3A1

Probe Details

Chemical Probes Portal ID:

CPP2147

Probe alias:

SERD, KE9, cpd 30b

PubChem CID:

86287635

ChEMBL ID:

CHEMBL3623004

SMILES string:

O=C(O)/C=C/C1=CC(F)=C([C@H]2N(CC(C)(F)C)[C@H](C)CC3=C2NC4=C3C=CC=C4)C(F)=C1

InChi Key:

DFBDRVGWBHBJNR-BBNFHIFMSA-N

Physico-chemical properties

Solubility - concentration:

110 uM

NMR:

1H NMR (400 MHz, DMSO-d6) 1.07–1.16 (3H, m), 1.18–1.29 (6H, m), 2.39 (1H, dd), 2.62 (1H, dd), 2.92 (2H, dd), 3.56 (1H, d), 5.26 (1H, s), 6.70 (1H, d), 7.02 (2H, dd), 7.22 (1H, d), 7.47 (3H, dd), 7.58 (1H, d), 10.60 (1H, s), 12.60 (1H, s)

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

pIC50

9.17 (0.8 nm)

Potency assay:

ERα LanthaScreen Assay to Measure ERα Binding

PDB ID for probe-target interaction (3D structure):

5ACC

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

High selectivity of AZD9496 over other tested nuclear hormone receptors: androgen receptor (AR), IC50 = 30 μM; glucocorticoid receptor (GR), IC50 = 9.2 μM; progesterone receptor (PR), IC50 = 0.54 μM (cf. estrogen receptor (ERα), IC50 = 0.0008 μM).

In cell validation

On target activity in cells

Potency in cells:

pIC50

9.86 (0.11 nM) ER downregulation, 9.55 (0.28 nM) PR antagonism, 10.4 (0.04 nM) anti-proliferation

Potency assay (cells):

Measurement of Endogenous ERα and PR Levels in a Multiplexed Cell Assay, ERα Functional Antagonism Cell Assay cell proliferation assay

Target engagement assay (cells):

Tamoxifen significantly lowered the IC50 value, as expected, if AZD9496 and Tamoxifen are competing for binding to the ligand-binding domain

Off target activity in cells

Probe Selectivity in Cell:

No significant growth inhibition was seen in any ER− cell lines (EC50 > 10 μmol/L) in contrast to the low nanomolar activity seen in a range of ER+ cell lines.

In vivo validation

Organism:

Rat (R)Mouse (M)Dog (D)

Dose:

5-100 mg/Kg

Route of delivery:

OralIntravenous

Systemic clearance:

1 (R), 43 (M), 0.28 (D) ml/min/Kg

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.5b00984 10.1158/0008-5472.CAN-15-2357

Reference (PMID):

26407012 27020862

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

The compound AZD9496 was the lead candidate for orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant. Most recently, the compound was put on clinical hold and replaced by AZD9833, a backup compound with a superior profile for safety and efficacy. In addition, there is excellent cellular data using two cell lines (MCF-7 and CAMA-1) for AZD9833. AZD9496 should be replaced by AZD9833 as the chemical probe; it still possesses very good properties can be used as a secondary probe.

Aug 4 2021 - 9:14pm

AZD9496

Probe Availability

Probe Information

Target Details

ER; ESR; Era; ESRA; ESTRR; NR3A1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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AZD9496

Probe Availability

Probe Information

Target Details

ER; ESR; Era; ESRA; ESTRR; NR3A1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?