astemizole   Click here for help

GtoPdb Ligand ID: 2603

Synonyms: Hismanal®
Approved drug PDB Ligand
astemizole is an approved drug
Compound class: Synthetic organic
Comment: Astemizole was originally identified as a histamine H1 receptor antagonist. Astemizole use as an antihistamine was withdrawn from the US market in 1999 as it caused arrhythmias, probably due to blocking the hERG potassium channel (Kv11.1) [5].

A 2014 publication showed that astemizole's anti-proliferative effects in cancer cells is due to disruption of a protein-protein interaction required for the formation of the active polycomb repressive complex 2 (PRC2) [3]. PRC2 contains the histone methyltransferase EZH2, which is responsible for catalytic trimethylation of lysine 27 on histone H3 (H3K27me3), an epigenetic modification that is a hallmark of silent chromatin. Aberrant PRC2 activity is associated with cancer initiation and progression. Astemizole was shown to inhibit the interaction between EZH2 and a PRC2 structural protein called embryonic ectoderm development (EED) [1], and that this action destabilizes PRC2 and reduces its methylation activity.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

astemizole is commercially available from our sponsors

2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 3
Hydrogen bond donors 1
Rotatable bonds 8
Topological polar surface area 42.32
Molecular weight 458.25
XLogP 5.81
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES COc1ccc(cc1)CCN1CCC(CC1)Nc1nc2c(n1Cc1ccc(cc1)F)cccc2
Isomeric SMILES COc1ccc(cc1)CCN1CCC(CC1)Nc1nc2c(n1Cc1ccc(cc1)F)cccc2
InChI InChI=1S/C28H31FN4O/c1-34-25-12-8-21(9-13-25)14-17-32-18-15-24(16-19-32)30-28-31-26-4-2-3-5-27(26)33(28)20-22-6-10-23(29)11-7-22/h2-13,24H,14-20H2,1H3,(H,30,31)
InChI Key GXDALQBWZGODGZ-UHFFFAOYSA-N
References
1. Cao Q, Wang X, Zhao M, Yang R, Malik R, Qiao Y, Poliakov A, Yocum AK, Li Y, Chen W et al.. (2014)
The central role of EED in the orchestration of polycomb group complexes.
Nat Commun, 5: 3127. [PMID:24457600]
2. García-Ferreiro RE, Kerschensteiner D, Major F, Monje F, Stühmer W, Pardo LA. (2004)
Mechanism of block of hEag1 K+ channels by imipramine and astemizole.
J Gen Physiol, 124 (4): 301-17. [PMID:15365094]
3. Kong X, Chen L, Jiao L, Jiang X, Lian F, Lu J, Zhu K, Du D, Liu J, Ding H et al.. (2014)
Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2.
J Med Chem, 57 (22): 9512-21. [PMID:25369470]
4. Pearlstein R, Vaz R, Rampe D. (2003)
Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior.
J Med Chem, 46 (11): 2017-22. [PMID:12747773]
5. Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT. (1999)
Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole.
J Cardiovasc Electrophysiol, 10 (6): 836-43. [PMID:10376921]