olaparib   Click here for help

GtoPdb Ligand ID: 7519

Synonyms: AZD-2281 | AZD2281 | Lynparza®
Approved drug PDB Ligand
olaparib is an approved drug (EMA & FDA (2014))
Compound class: Synthetic organic
Comment: Olaparib is an AstraZeneca poly ADP ribose polymerase (PARP) inhibitor [9]. It is discussed in the AZ 2014 review paper [3].
Cancer cells carrying BRCA mutations become more reliant on PARP activity to maintain DNA repair [11], so this enzyme represents a vulnerable target for pharmaceutical intervention in these cancers.
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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

olaparib 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 Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). 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 6
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 86.37
Molecular weight 434.18
XLogP 2.44
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
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.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES O=C(N1CCN(CC1)C(=O)c1cc(ccc1F)Cc1n[nH]c(=O)c2c1cccc2)C1CC1
Isomeric SMILES O=C(N1CCN(CC1)C(=O)c1cc(ccc1F)Cc1n[nH]c(=O)c2c1cccc2)C1CC1
InChI InChI=1S/C24H23FN4O3/c25-20-8-5-15(14-21-17-3-1-2-4-18(17)22(30)27-26-21)13-19(20)24(32)29-11-9-28(10-12-29)23(31)16-6-7-16/h1-5,8,13,16H,6-7,9-12,14H2,(H,27,30)
InChI Key FDLYAMZZIXQODN-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
No information available.
Summary of Clinical Use Click here for help
In December 2014, both the EMA and US FDA granted olaparib approval for the treatment of advanced ovarian cancer in patients with BRCA mutations, detected using an approved mutation detection test.
FDA approval (August 2017) was granted for use as maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
FDA approval was expanded in January 2018, to include treatment of patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-ve metastatic breast cancer (treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting).
Following encouraging results in patients with advanced and difficult to treat prostate cancers carrying DNA repair defects [2,6-8], and Phase 3 evaluations for this indication, the FDA approved olaparib in May 2020, as a treatment for DNA repair gene-mutated mCRPC (where disease has progressed following prior treatment with enzalutamide or abiraterone).
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Olaparib is a poly ADP ribose polymerase (PARP) inhibitor [9]. PARP is involved in repairing single-strand DNA breaks (nicks). In cells with mutations in other DNA repair enzymes such as the BRCA and PALB2 (Q86YC2) mutations in breast, ovarian and prostate cancers [1], PARP becomes more important for the DNA repair process. In such malignant cells, inhibition of PARP may therefore result in cell death due to accumulated DNA damage. Some PARP inhibitors cause irreversible binding of the enzyme to the DNA in addition to catalytic inhibition [10]. This may result in accumulation of toxic PARP-DNA complexes.
External links Click here for help
For extended ADME data see the following:

Electronic Medicines Compendium (eMC)
Drugs.com
European Medicines Agency (EMA)