Ligand id: 7519

Name: olaparib

Structure and Physico-chemical Properties

2D Structure
Calculated Physico-chemical Properties
Hydrogen bond acceptors 7
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 69.72
Molecular weight 434.18
XLogP 3.39
No. Lipinski's rules broken 0

Molecular properties generated using the CDK

No information available.
Summary of Clinical Use
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.
Cancer cells carrying BRCA mutations become more reliant on PARP activity to maintain DNA repair [7], so this enzyme represents a vulnerable target for pharmaceutical intervention in these cancers.
Preliminary, and as yet unpublished results from a clinical trial in patients with recurrent ovarian cancer, combining olaparib and cediranib (a neo-angiogenesis inhibitor) suggest a significant extension of progression-free survival and may offer an alternative to chemotherapy.
The drug has also shown encouraging results in patients with advanced and difficult to treat prostate cancers carrying DNA-repair defects (Phase II clinical trial NCT01682772) [4].
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).
Mechanism Of Action and Pharmacodynamic Effects
Olaparib is a poly ADP ribose polymerase (PARP) inhibitor [5]. 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 [6]. This may result in accumulation of toxic PARP-DNA complexes.