Veliparib

Veliparib : Catalytic, PARP-DNA complex trapping inhibitor of PARP1 and PARP2

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(2 ratings)

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Information

PARP1
PARP2

Catalytic inhibitor, PARP-DNA complex trapping

Probe Availability:

In Vitro Validations

Uniprot ID: P09874

Target Class: Other post-translational modification

Target SubClass: PARP

Potency: Ki

Potency Value: 5.2 nM

Potency Assay: Biochemical Assay

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

Structure-activity relationship: Yes

Target aliases:

Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/acs.jmedchem.6b00990

Uniprot ID: P09874

Target Class: Other post-translational modification

Target SubClass: PARP

Potency: IC 50

Potency Value: 3.3 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/acs.jmedchem.6b00990

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : Ki 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 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). 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).

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

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.

(last updated: 1 Aug 2016 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP 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.

(last updated: 9 Sept 2016 )

SERP Ratings

In Cell Rating

SERP Comments:

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. 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.

(last updated: 17 Jan 2017 )

SERP Comments:

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.

(last updated: 18 Jan 2017 )