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 [8]. 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 [10], so this enzyme represents a vulnerable target for pharmaceutical intervention in these cancers.
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2D Structure
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Physico-chemical Properties
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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
SMILES / InChI / InChIKey
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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
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 [2,5-7], 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 [8]. 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 [9]. This may result in accumulation of toxic PARP-DNA complexes.
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