Veliparib

Reagent Authentication Certificate:

Chemical Probes Portal Veliparib.pdf

Protein target name:

PARP1, PARP2

Mechanism of action:

Catalytic inhibitorPARP-DNA complex trapping

Recommended Concentration for use in cells:

10-100 nM

Probe Availability

Cayman (912445-05-7)

MedChem Express (912444-00-9)

Probe Information

Target and Probe Information

Target Details

Target class:

ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1, ADPRT2, ADPRTL2, ADPRTL3, ARTD2, PARP-2, pADPRT-2

Probe Details

Chemical Probes Portal ID:

CPP594

Probe alias:

912444-00-9; ABT-888; ABT 888; ABT888; UNII-01O4K0631N

PubChem CID:

11960529

ChEMBL ID:

CHEMBL506871

SMILES string:

C[C@@]1(CCCN1)C2=NC3=C(C=CC=C3N2)C(=O)N

InChi Key:

JNAHVYVRKWKWKQ-CYBMUJFWSA-N

Orthogonal probe:

OlaparibTalazoparibNiraparib

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

PARP1 5.2 nM, PARP2 2.9 nM

Potency assay:

In in vitro ADP ribosylation assays, veliparib had the following activity: IC50 PARP1 (full length)=3.3 nM, PARP2 (full length)=17.5 nM

PDB ID for probe-target interaction (3D structure):

5LX6

Structure-activity relationship:

Yes

Off target activity

Potency (off target):

Off target protein and potency:

SIRT2 >5,000 nM

Potency assay (off target):

In ADP ribosylation assays for PARP family members, veliparib was >100-fold selective for PARP1 and PARP2 (IC50: PARP3=2040 nM, PARP4=3500 nM, TNKS1=10740 nM, TNKS2=24000 nM, PARP10=1900 nM, PARP12=59,400 nM, PARP14=89000 nM with no detectable activity against PARP15 or PARP16).

Probe Selectivity in Vitro:

In a panel of 74 receptors, veliparib inhibited only 3 by more than 50% at 10 uM: H1 (61%; IC50 = 5.3 uM), 5-HT1A (91%; IC50 = 1.2 uM), and 5-HT7 (84%; IC50 = 1.5 uM).

In cell validation

On target activity in cells

Potency in cells:

IC50

PARP 5.9 nM

Potency assay (cells):

In LoVo cells, PAR synthesis assay.

Target engagement assay (cells):

Not available

In vivo validation

Organism:

CD1 mouse, rat

Dose:

10 mg/kg (mice), 5 mg/kg (rat)

Route of delivery:

OralIntravenous

Plasma half life:

1.6 h (mouse IV), 1.2 h (rat IV)1.3 h (mouse oral), 1.6 h (rat oral)

Systemic clearance:

4.1 L/h/kg (mouse IV), 2.0 L/h/kg (rat IV)

Ratio of probe in organ to plasma (O:P):

0.72 ug/gm (brain), 3 ug/gm (tum), 1.36 ug/mL (p)

Cmax:

1.6 ug/mL (mouse, oral), 0.5 ug/ml (rat, oral)

Tmax:

0.3 h (mouse, oral), 0.8 h (rat, oral)

Organ of Interest

Organ (O):

xenograft tumorbrainplasma

Target engagement assay:

Indirect: in B16F10 tumors, velaparib inhibited PAR as detected in western blot.

Primary Reference

Reference (doi):

10.1158/1078-0432.CCR-06-3039 10.1021/acs.jmedchem.6b00990

Reference (PMID):

11960529 28001384

External Resources

Available data:

GDSC

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

Velaparib is not overly potent in vivo as a a single agent but potentiates both chemo- and radiotherapy. Like other PARP inhibitors, veliparib is a potent inhibitor of PARP1 and 2 but not the other 15 family members. Critically, velparib appears to inhibit PARP as an inhibitor of catalytic function and does not enhance PARP trapping at the site of DNA damage. Given this, veliparib is strongly recommended for the deconvolution of the catalytic roles of PARP in in vitro experiments.

Aug 5 2016 - 3:06pm

Veliparib 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.

Sep 8 2016 - 11:36am

Veliparib is a potent dual PARP1/2 inhibitor. It is highly recommended for studying the function of these targets in vitro. Veliparib has also shown utility in in vivo studies and even some degree of CNS penetrance.

Sep 9 2016 - 6:17pm

Veliparib is a PARP1/2 inhibitor with selectivity sufficient for cellular work to interrogate PARP1/2. While target engagement has been shown in vivo at modest doses, the lack of receptor profiling limits my recommendation for Veliparib to be used as an in vivo probe.

Jan 18 2017 - 12:04pm

Veliparib

Probe Availability

Probe Information

Target Details

ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1, ADPRT2, ADPRTL2, ADPRTL3, ARTD2, PARP-2, pADPRT-2

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

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Veliparib

Probe Availability

Probe Information

Target Details

ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1, ADPRT2, ADPRTL2, ADPRTL3, ARTD2, PARP-2, pADPRT-2

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?