Olaparib

Olaparib : Catalytic, PARP-DNA complex trapping inhibitor of PARP1 and PARP

Structure

Information

  • PARP1
  • PARP2
  • Catalytic inhibitor, PARP-DNA complex trapping

In Vitro Validations

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: IC 50
Potency Value: 5 nM
Potency Assay: In vitro biochemical assays using 3H-NAD or biotinylated-NAD.
PDB ID for probe-target interaction (3D structure): 7KK4
Structure-activity relationship: Yes
Target aliases:
Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/jm8001263

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: IC 50
Potency Value: 1.4 nM
Potency Assay: ADP ribosylation assays, PARP1 (full-length)
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/jm8001263

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 TNKS 1.5 uM, PARP3 230 nM, PARP4 410 nM, TNKS1 1230 nM, PARP10 1250 nM
Potency assay (off target): In vitro activity assay with biotinylated-NAD. In in vitro ADP ribosylation assays, oliparib was only 15-20-fold selective for PARP1/2 over other PARP proteins. (IC50: TNKS2=2340 nM, PARP10=9300 nM, PARP12=10050 nM, PARP15=17600 nM, PARP16=5100 nM, with no activity detected against PARP14).
Probe Selectivity in Vitro:
In vitro activity assay with biotinylated-NAD. In in vitro ADP ribosylation assays, olaparib was only 15-20-fold selective for PARP1/2 over other PARP proteins. (IC50: TNKS2=2340 nM, PARP10=9300 nM, PARP12=10050 nM, PARP15=17600 nM, PARP16=5100 nM, with no activity detected against PARP14).
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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 1 Aug 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 20 Dec 2016 )

SERP Comments:

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.

(last updated: 19 Jan 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Olaparib has actvity against PARPs 1, 2, 3 and 4; it has little activity against other members of the PARP family.

(last updated: 15 Jun 2017 )