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Niraparib

Niraparib : Inhibitor of PARP1 and PARP2

Structure

Information

  • PARP1
  • PARP2
  • Inhibitor
  • Up to 50 nM

In Vitro Validations

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: IC 50
Potency Value: 3.2 nM
Potency Assay: SPA assay.
PDB ID for probe-target interaction (3D structure): 4R6E
Structure-activity relationship: Yes
Target aliases:
Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/jm901188v

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: IC 50
Potency Value: 3.8 nM
Potency Assay: TCA precipitation assays
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/jm901188v

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: IC 50
Potency Value: 16.7 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/jm901188v

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 TNKS 570 nM, PARP3 296 nM, PARP4 446 nM, PARP12 79 nM
Potency assay (off target): In TCA precipitation assays, MK-4827 was at least 300-fold selective for PARP1 and PARP2 over TNKS, V-PARP (IC50 = 330 nM) and PARP3 (IC50 = 1,300 nM). In ADP ribosylation assays, niraparib was ~100-fold selective for PARP1/2 over other PARP proteins (IC50: PARP3=296 nM, PARP4=446 nM, TNKS1=2355 nM, TNKS2=5130 nM, PARP10=1900 nM, PARP12=79 nM, PARP14=17300 nM, PARP15=29200 nM, with no detectable activity against PARP16).
Probe Selectivity in Vitro:
In TCA precipitation assays, MK-4827 was at least 300-fold selective for PARP1 and PARP2 over TNKS, V-PARP (IC50 = 330 nM) and PARP3 (IC50 = 1,300 nM). In ADP ribosylation assays, niraparib was ~100-fold selective for PARP1/2 over other PARP proteins (IC50: PARP3=296 nM, PARP4=446 nM, TNKS1=2355 nM, TNKS2=5130 nM, PARP10=1900 nM, PARP12=79 nM, PARP14=17300 nM, PARP15=29200 nM, with no detectable activity against PARP16).
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Though this looks like a good tool compound for PARPs, due to the issues with other PARP inhibitors, it would be a good idea to use this probe side-by-side with a structurally distinct inhibitor to cross-validate results.

(last updated: 17 Aug 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Niraparib is a PARP 1/2 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: 3 Jan 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

The compound is reported to be a potent and selective PARP1/2 inhibitor. I have no significant concerns about recommending this compound for use as a chemical probe. In an ideal world, an inactive, closely related analogue would be available for use as a "negative control" but I have been unable to identify one from the literature. To mitigate against the risk of effects caused by unknown, off-target activity (broad profiling has not, to my knowledge, been published), carrying out studies using this alongside a structurally distinct PARP inhibitor is recommended, where possible. I completely agree with the current reviews recommending researchers to understand their needs and combine their selection with an orthogonal (positive) control or another PARP1/2 inhibitor that acts via a different mechanism or has a different chemotype. If possible, I suggest including a negative control for cell-based assays. Niraparib is in clinical trials. Does this mean that it is a chemical probe? In this case, it does not satisfy the criteria outlined by Workman and Collins (DOI 10.1016/j.chembiol.2010.05.013). Based on Thorsell et al. (DOI: : 10.1021/acs.jmedchem.6b00990), niraparib inhibits PARP12. Within the family of PARPs, PARP1 and PARP2 are sub-branches on the same main branch while PARP12 is much further removed. To my knowledge, off-target screening data characterizing its activity against kinases, GPCRs, and other likely targets has also not been published. There is also potential off-target inhibition on deoxycitidine kinase (DOI:10.1016/j.chembiol.2016.10.011).

(last updated: 16 May 2017 )