General
Preferred name
OLAPARIB
Synonyms
KU0059436, AZD-2281 ()
KU0059436, AZD2281 ()
AZD2281 ()
KU-0059436 ()
KU0059436 ()
Olaparib (AZD2281) ()
AZD 2281 ()
AZD-2281 ()
KU 59436 ()
KU-59436 ()
LYNPARZA ()
KU59436 ()
O-9201 ()
AZ2281 ()
NSC-747856 ()
OLAPARIB COMPONENT OF KEYLYNK-010 ()
AZ-2281 ()
KEYLYNK-010 COMPONENT OLAPARIB ()
Olaparib-d4 ()
P&D ID
PD003576
CAS
763113-22-0
937799-91-2
1021843-02-6
Tags
available
probe
drug
Approved by
PMDA
EMA
FDA
First approval
2014
Drug Status
approved
Drug indication
Ovarian cancer
Prostate cancer
Pancreatic cancer
Max Phase
Phase 4
Probe info
Probe selectivity
family-selective
Probe type
P&D approved
calculated probe
experimental probe
Probe sources
Probe targets
[[ compound.targets[t].gene_name ]]
Probe control
Probe control not defined
Orthogonal probes
10
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA
Catalytic inhibitor;PARP-DNA complex trapping
ROE
From the administered dose, approximately 86% of the administered dose is recovered after 7 days from which 44% is found in the urine and 42% is obtained in feces.[L5089]
PHARMACODYNAMICS
The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 mg and in 109 patients following multiple dosing of 300 mg twice daily [FDA Label]. No clinically relevant effect of olaparib on QT interval was observed [FDA Label].
HALF-LIFE
The reported elimination half-life ranges between 5 to 11 hours.[A35290]
MOA
Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair [FDA Label]. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy [FDA Label]. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA [FDA Label]. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death [FDA Label].
METABOLISM
Olaparib is extensively metabolized in the liver by the action of CYP3A isoenzymes.[F2974] From the administered dose, the unchanged form of olaparib accounted for 70% of the circulating dose and it was considered the major component in urine and feces.[L5089] The metabolic pathway of olaparib is mainly attributable to oxidation reactions with subsequent glucuronide and sulfate conjugation. However, the over 20 metabolites found in plasma, urine, and feces represented a minor portion of the administered dose. The major circulating metabolites were represented by the mono-oxygenated form and the piperazin-3-ol form.[L5089]
ABSORPTION
Following oral administration, the absorption of olaparib is very rapid and can reach a peak concentration ranging between 4.7 and 9.1 mcg/ml after 1-3 hours. The reported AUC of olaparib after a dose of 200 mg is of 25.8 mcg.h/L and this AUC can be increased by 26% with constant administration. The consumption of a high-fat diet with olaparib can only decrease the tmax but do not have an effect in the peak concentration.[A35290]
METABOLISM
Olaparib is extensively metabolized in the liver by the action of CYP3A isoenzymes.[F2974] From the administered dose, the unchanged form of olaparib accounted for 70% of the circulating dose and it was considered the major component in urine and feces.[L5089]; ; The metabolic pathway of olaparib is mainly attributable to oxidation reactions with subsequent glucuronide and sulfate conjugation. However, the over 20 metabolites found in plasma, urine, and feces represented a minor portion of the administered dose. The major circulating metabolites were represented by the mono-oxygenated form and the piperazin-3-ol form.[L5089]
DESCRIPTION
Olaparib is an AstraZeneca poly ADP ribose polymerase (PARP) inhibitor . It is discussed in the AZ 2014 review paper .
Cancer cells carrying BRCA mutations become more reliant on PARP activity to maintain DNA repair , so this enzyme represents a vulnerable target for pharmaceutical intervention in these cancers. (GtoPdb)
Cancer cells carrying BRCA mutations become more reliant on PARP activity to maintain DNA repair , so this enzyme represents a vulnerable target for pharmaceutical intervention in these cancers. (GtoPdb)
INDICATION
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of: (I) Ovarian cancer, in which the medication is intended for [a] the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy, or [b] for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy [FDA Label]. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib [FDA Label]. [II] Breast cancer, in which the medication is intended for use in patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment [FDA Label]. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib [FDA Label].
TOXICITY
The most commonly reported side effects reported during clinical trials included cough, constipation, dysgeusia, peripheral deem, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash [FDA Label] [L5089, F2974]. Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in 2% of patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers [FDA Label] [L5089, F2974]. The majority of cases were fatal and the duration of therapy with olaparib in patients who developed secondary cancers varied from <6 months to >2 years [FDA Label] [L5089, F2974]. Complete blood count should be tested at baseline and monthly following therapy initiation to monitor for MDS/AML [FDA Label] [L5089, F2974]. Pneumonitis, including fatal cases, occurred in <1% of patients treated with olaparib [FDA Label] [L5089, F2974]. Patients should be monitored for new or worsening respiratory symptoms such as dyspnea, fever, cough, or wheezing [FDA Label] [L5089, F2974]. Olaparib was found to be teratogenic and causes embryo-fetal toxicity in rats [FDA Label] [L5089, F2974]. It should, therefore, be avoided during pregnancy and its use should be combined with effective contraception during treatment [FDA Label] [L5089, F2974].
INDICATION
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of:; ; (I) Ovarian cancer, in which the medication is intended for [a] the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy, or [b] for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy [FDA Label]. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib [FDA Label].; ; [II] Breast cancer, in which the medication is intended for use in patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment [FDA Label]. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib [FDA Label].
COMMENT
Olaparib provides an effective tool compound for investigating the role of the PARPs in DNA repair and other biological contexts. However, olaparib inhibits predominantly PARPs 1 and 2, leaving the other 15 family members, to potentially compensate to some extent for this inhibition. There is some evidence that olaparib works primarily through trapping of PARP on damaged DNA, sequestering the enzyme, rather than through direct inhibition of catalytic function. Given this, for certain experiments it is advisable to use veliparib, either as a replacement or for parallel studies, which appears not to trap PARP but to inhibit it's catalytic function. Aug 5 2016 - 3:08pm; Olaparib is a PARP 1/2/3 inhibitor. This agent is an excellent tool to study PARP inhibition in both the cellular and in vivo setting. However, an important study about the mechanism of these probes appeared in 2012 (Murai et al., Cancer Res. 2012, 72, 5588-5599). In this study, the authors examined the ability of niraparib, olaparib and veliparib to trap PARP1/2 enzymes at the site of DNA damage as opposed to examining merely their activity as inhibitors of the catalytic function of the enzyme. The authors found that the cellular toxicity tracked with the trapping potential (which was different for each drug) rather than each drugs catalytic efficiency (which was similar for each drug). The ranking of each drug for trapping efficiency was found to be niraparib > olaparib >> veliparib. Investigators should thoroughly evaluate their needs when choosing the appropriate PARP inhibitor based upon this altered mechanistic insight. Sep 8 2016 - 11:33am; Olaparib has actvity against PARPs 1, 2, 3 and 4; it has little activity against other members of the PARP family. Dec 26 2016 - 12:10pm; Portal staff comment: A new publication appeared in December 2016 (PMID 28001384) indicating that veliparib and niraparib are more selective than olaparib among PARP family proteins. Jan 19 2017 - 3:24pm
MOA
Catalytic inhibitor, PARP-DNA complex trapping
(Chemical Probes.org)
DESCRIPTION
inhibitor of poly (ADP-ribose) polymerase 1 and 2
(Informer Set)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
265
Organisms
0
Compound Sets
28
AdooQ Bioactive Compound Library
Axon Medchem Screening Library
ChEMBL Approved Drugs
ChEMBL Drugs
Chemical Probes.org
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
EU-OPENSCREEN Bioactive Compound Library
Guide to Pharmacology
High-quality chemical probes
Informer Set
LINCS compound set
LSP-MoA library (Laboratory of Systems Pharmacology)
MedChem Express Bioactive Compound Library
NCATS Inxight Approved Drugs
NIH Approved Oncology Drugs
Novartis Chemogenetic Library (NIBR MoA Box)
ReFrame library
Selleckchem Bioactive Compound Library
TargetMol Bioactive Compound Library
Tool Compound Set
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
42
Molecular Weight
434.18
Hydrogen Bond Acceptors
4
Hydrogen Bond Donors
1
Rotatable Bonds
4
Ring Count
5
Aromatic Ring Count
3
cLogP
2.35
TPSA
86.37
Fraction CSP3
0.33
Chiral centers
0.0
Largest ring
6.0
QED
0.68
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
PARP1
PARP2
PARP1, PARP2
Poly [ADP-ribose] polymerase-1
Poly [ADP-ribose] polymerase 2
Mitophagy
Autophagy,Mitophagy,PARP
Compound status
clinical
Pathway
Genome integrity
Chromatin/Epigenetic
DNA Damage/DNA Repair
Autophagy
Cell Cycle/DNA Damage
Epigenetics
MOA
PARP
Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors
Poly(ADP-ribose)polymerase-2 (PARP-2) Inhibitors
PARP inhibitor
Member status
member
Indication
ovarian cancer
Orthogonal probe
Niraparib
Target class
Other post-translational modification
Other post-translational modification, Other post-translational modification
Target subclass
PARP, PARP
Source data
